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--- playground:playground [2015/03/19 15:35]
127.0.0.1 external edit
+++ playground:playground [2023/02/01 22:54] (current)
desaia14
@@ Line 1: / Line 1: @@
 ====== PlayGround ======
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+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Introduction: <o:p></o:p></span>'''<p class=MsoNormal style='margin-bottom:12.0pt'><span lang=EN style='font-size:
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+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Gram-Negative Bacteria:<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>For
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+the cell its shape, selectively allows the passage of molecules into and out of
+the cytoplasm, and protects the cell</span><!--[if supportFields]><span
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+\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE><span
+style='background:white;mso-highlight:white'>Silhavy</span></span><span
+style='background:white;mso-highlight:white'>, <span class=SpellE>Kahne</span>,
+& Walker, 2010). The bacteria fall into two groups, depending on their cell
+envelope: Gram-negative bacteria and Gram-positive bacteria. <i
+style='mso-bidi-font-style:normal'>E. coli'' is an example of a Gram-negative
+bacteria</span></span><!--[if supportFields]><span lang=EN style='font-size:
+.0pt;line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'><span style='mso-element:
+field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"CJIH8jEe","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in
+Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(<span class=SpellE>Silhavy</span>, <span class=SpellE>Kahne</span>, &
+Walker, 2010).<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><i style='mso-bidi-font-style:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>E.
+coli</span>''<span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'>’s cell envelope, shown in figure X,
+consists of an inner membrane (IM), a peptidoglycan cell wall, and an outer
+membrane (OM) which is unique to Gram-negative bacteria</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"k70Th6wE","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in
+Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(<span class=SpellE>Silhavy</span>, <span class=SpellE>Kahne</span>, &
+Walker, 2010). The IM is a phospholipid (PL) bilayer</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"B661XGj7","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology,
+Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Bishop, 2020). Proteins responsible for energy production, lipid biosynthesis,
+protein secretion, and transport are located in the IM due to a lack of
+intracellular organelles</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"mcVZ8LiH","properties":{"formattedCitation":"\\super
+,2\\nosupersub{}","plainCitation":"1,2","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to protect
+these organisms from their unpredictable and often hostile environment. The
+cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}},{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology, Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1,2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Bishop, 2020; <span class=SpellE>Silhavy</span>, <span class=SpellE>Kahne</span>,
+& Walker, 2010). The peptidoglycan cell wall, found in the periplasmic
+space between the IM and OM, is made up of repeating units of the disaccharide
+N-acetyl glucosamine-N-acetyl muramic acid (NAG-NAM), cross-linked by
+pentapeptide side chains</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"jhF990s7","properties":{"formattedCitation":"\\super
+,3\\nosupersub{}","plainCitation":"1,3","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in
+Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}},{"id":619,"uris":["http://zotero.org/users/local/DWdd4k1w/items/HWCQ9FUI"],"itemData":{"id":619,"type":"article-journal","abstract":"Gram-negative
+bacteria are surrounded by a complex cell envelope that includes two membranes.
+The outer membrane prevents many drugs from entering these cells and is thus a
+major determinant of their intrinsic antibiotic resistance. This barrier
+function is imparted by the asymmetric architecture of the membrane with
+lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner
+leaflet. The LPS and phospholipid synthesis pathways share an intermediate.
+Proper membrane biogenesis therefore requires that the flux through each
+pathway be balanced. In Escherichia coli, a major control point in establishing
+this balance is the committed step of LPS synthesis mediated by LpxC. Levels of
+this enzyme are controlled through its degradation by the inner membrane
+protease FtsH and its presumed adapter protein LapB (YciM). How turnover of
+LpxC is controlled has remained unclear for many years. Here, we demonstrate
+that the essential protein of unknown function YejM (PbgA) participates in this
+regulatory pathway. Suppressors of YejM essentiality were identified in lpxC
+and lapB, and LpxC overproduction was shown to be sufficient to allow survival
+of ΔyejM mutants. Furthermore, the stability of LpxC was shown to be
+reduced in cells lacking YejM, and genetic and physical interactions between
+LapB and YejM were detected. Taken together, our results are consistent with a
+model in which YejM directly modulates LpxC turnover by FtsH-LapB to regulate
+LPS synthesis and maintain membrane homeostasis.\nIMPORTANCE The outer membrane
+is a major determinant of the intrinsic antibiotic resistance of Gram-negative
+bacteria. It is composed of both lipopolysaccharide (LPS) and phospholipid, and
+the synthesis of these lipid species must be balanced for the membrane to
+maintain its barrier function in blocking drug entry. In this study, we
+identified an essential protein of unknown function as a key new factor in
+modulating LPS synthesis in the model bacterium Escherichia coli. Our results
+provide novel insight into how this organism and most likely other
+Gram-negative bacteria maintain membrane homeostasis and their intrinsic
+resistance to
+antibiotics.","container-title":"mBio","DOI":"10.1128/mBio.00939-20","issue":"3","note":"publisher:
+American Society for Microbiology","page":"e00939-20","source":"journals.asm.org
+(Atypon)","title":"An Essential Membrane Protein Modulates
+the Proteolysis of LpxC to Control Lipopolysaccharide Synthesis in Escherichia
+coli","URL":"https://journals.asm.org/doi/10.1128/mBio.00939-20","volume":"11","author":[{"family":"Fivenson","given":"Elayne
+M."},{"family":"Bernhardt","given":"Thomas
+G."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",5,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1,3</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Fivenson</span>,
+& Bernhardt, 2020; <span class=SpellE>Silhavy</span>, <span class=SpellE>Kahne</span>,
+& Walker, 2010). This rigid cell wall is responsible for the maintenance of
+<i style='mso-bidi-font-style:normal'>E. coli''’s characteristic rod shape</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"QysnGSot","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in
+Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Silhavy</span>,
+<span class=SpellE>Kahne</span>, & Walker, 2010). The peptidoglycan layer
+is connected to the OM through a lipoprotein, murein/Braun’s lipoprotein (<span
+class=SpellE>Lpp</span>)</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"ExJWWN7s","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in
+Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Silhavy</span>,
+<span class=SpellE>Kahne</span>, & Walker, 2010). The OM is an asymmetric
+lipid bilayer that is essential for <i style='mso-bidi-font-style:normal'>E.coli''’s
+survival because it acts as the first line of <span class=SpellE>defence</span>
+against external threats</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"G4EUP7vu","properties":{"formattedCitation":"\\super
+,2\\nosupersub{}","plainCitation":"1,2","noteIndex":0},"citationItems":[{"id":614,"uris":["http://zotero.org/users/local/DWdd4k1w/items/H9G2P5QM"],"itemData":{"id":614,"type":"article-journal","abstract":"The
+bacteria cell envelope is a complex multilayered structure that serves to
+protect these organisms from their unpredictable and often hostile environment.
+The cell envelopes of most bacteria fall into one of two major groups.
+Gram-negative bacteria are surrounded by a thin peptidoglycan cell wall, which
+itself is surrounded by an outer membrane containing lipopolysaccharide.
+Gram-positive bacteria lack an outer membrane but are surrounded by layers of
+peptidoglycan many times thicker than is found in the Gram-negatives. Threading
+through these layers of peptidoglycan are long anionic polymers, called
+teichoic acids. The composition and organization of these envelope layers and
+recent insights into the mechanisms of cell envelope assembly are
+discussed.","container-title":"Cold Spring Harbor
+Perspectives in
+Biology","DOI":"10.1101/cshperspect.a000414","ISSN":",
+-0264","issue":"5","journalAbbreviation":"Cold
+Spring Harb Perspect
+Biol","language":"en","note":"Company:
+Cold Spring Harbor Laboratory Press\nDistributor: Cold Spring Harbor Laboratory
+Press\nInstitution: Cold Spring Harbor Laboratory Press\nLabel: Cold Spring
+Harbor Laboratory Press\npublisher: Cold Spring Harbor Lab\nPMID:
+20452953","page":"a000414","source":"cshperspectives.cshlp.org","title":"The
+Bacterial Cell
+Envelope","URL":"http://cshperspectives.cshlp.org/content/2/5/a000414","volume":"2","author":[{"family":"Silhavy","given":"Thomas
+J."},{"family":"Kahne","given":"Daniel"},{"family":"Walker","given":"Suzanne"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",1,5]]}}},{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology,
+Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>1,2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020; <span class=SpellE>Silhavy</span>,
+<span class=SpellE>Kahne</span>, & Walker, 2010). It prevents the entry or
+exit of large, hydrophobic molecules and works together with the peptidoglycan
+cell wall to provide mechanical strength to the bacterial cell, protecting it
+from osmotic lysis</span><!--[if supportFields]><span lang=EN style='font-size:
+.0pt;line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"Pm7E79sY","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":621,"uris":["http://zotero.org/users/local/DWdd4k1w/items/D7M3VN8M"],"itemData":{"id":621,"type":"article-journal","abstract":"Lipopolysaccharide
+(LPS) is an essential glycolipid present in the outer membrane (OM) of many
+Gram-negative bacteria. Balanced biosynthesis of LPS is critical for cell
+viability; too little LPS weakens the OM, while too much LPS is lethal. In
+Escherichia coli, this balance is maintained by the YciM/FtsH protease complex,
+which adjusts LPS levels by degrading the LPS biosynthesis enzyme LpxC. Here,
+we provide evidence that activity of the YciM/FtsH protease complex is
+inhibited by the essential protein YejM. Using strains in which LpxC activity
+is reduced, we show that yciM is epistatic to yejM, demonstrating that YejM
+acts upstream of YciM to prevent toxic overproduction of LPS. Previous studies
+have shown that this toxicity can be suppressed by deleting lpp, which codes
+for a highly abundant OM lipoprotein. It was assumed that deletion of lpp
+restores lipid balance by increasing the number of acyl chains available for
+glycerophospholipid biosynthesis. We show that this is not the case. Rather,
+our data suggest that preventing attachment of lpp to the peptidoglycan
+sacculus allows excess LPS to be shed in vesicles. We propose that this loss of
+OM material allows continued transport of LPS to the OM, thus preventing lethal
+accumulation of LPS within the inner membrane. Overall, our data justify the
+commitment of three essential inner membrane proteins to avoid toxic over- or
+underproduction of LPS.\nIMPORTANCE Gram-negative bacteria are encapsulated by
+an outer membrane (OM) that is impermeable to large and hydrophobic molecules.
+As such, these bacteria are intrinsically resistant to several clinically
+relevant antibiotics. To better understand how the OM is established or
+maintained, we sought to clarify the function of the essential protein YejM in
+Escherichia coli. Here, we show that YejM inhibits activity of the YciM/FtsH
+protease complex, which regulates synthesis of the essential OM glycolipid
+lipopolysaccharide (LPS). Our data suggest that disrupting proper communication
+between LPS synthesis and transport to the OM leads to accumulation of LPS
+within the inner membrane (IM). The lethality associated with this event can be
+suppressed by increasing OM vesiculation. Our research has identified a
+completely novel signaling pathway that we propose coordinates LPS synthesis
+and
+transport.","container-title":"mBio","DOI":"10.1128/mBio.00598-20","issue":"2","note":"publisher:
+American Society for Microbiology","page":"e00598-20","source":"journals.asm.org
+(Atypon)","title":"YejM Modulates Activity of the YciM/FtsH
+Protease Complex To Prevent Lethal Accumulation of
+Lipopolysaccharide","URL":"https://journals.asm.org/doi/10.1128/mBio.00598-20","volume":"11","author":[{"family":"Guest","given":"Randi
+L."},{"family":"Samé
+Guerra","given":"Daniel"},{"family":"Wissler","given":"Maria"},{"family":"Grimm","given":"Jacqueline"},{"family":"Silhavy","given":"Thomas
+J."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",4,14]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>4</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Guest et al., 2020). The OM is
+made of PLs in the inner leaflet and lipopolysaccharide (LPS) glycolipid
+molecules in the outer leaflet</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"jGfiKmxu","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":623,"uris":["http://zotero.org/users/local/DWdd4k1w/items/HUNH4ZWD"],"itemData":{"id":623,"type":"article-journal","abstract":"The
+cell envelope is the first line of defense between a bacterium and the
+world-at-large. Often, the initial steps that determine the outcome of chemical
+warfare, bacteriophage infections, and battles with other bacteria or the
+immune system greatly depend on the structure and composition of the bacterial
+cell surface. One of the most studied bacterial surface molecules is the
+glycolipid known as lipopolysaccharide (LPS), which is produced by most
+Gram-negative bacteria. Much of the initial attention LPS received in the early
+s was owed to its ability to stimulate the immune system, for which the
+glycolipid was commonly known as endotoxin. It was later discovered that LPS
+also creates a permeability barrier at the cell surface and is a main
+contributor to the innate resistance that Gram-negative bacteria display
+against many antimicrobials. Not surprisingly, these important properties of
+LPS have driven a vast and still prolific body of literature for more than a
+hundred years. LPS research has also led to pioneering studies in bacterial envelope
+biogenesis and physiology, mostly using Escherichia coli and Salmonella as
+model systems. In this review, we will focus on the fundamental knowledge we
+have gained from studies of the complex structure of the LPS molecule and the
+biochemical pathways for its synthesis, as well as the transport of LPS across
+the bacterial envelope and its assembly at the cell
+surface.","container-title":"EcoSal
+Plus","DOI":"10.1128/ecosalplus.ESP-0001-2018","issue":"1","note":"publisher:
+American Society for Microbiology","source":"journals.asm.org
+(Atypon)","title":"Function and Biogenesis of
+Lipopolysaccharides","URL":"https://journals.asm.org/doi/10.1128/ecosalplus.ESP-0001-2018","volume":"8","author":[{"family":"Bertani","given":"Blake"},{"family":"Ruiz","given":"Natividad"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2018",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>5</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bertani & Ruiz, 2018). The OM
+also consists of <span style='background:white;mso-highlight:white'>OM proteins
+(<span class=SpellE>Omps</span>), exopolysaccharides (EPS), flagella and type I
+fimbria</span></span><!--[if supportFields]><span lang=EN style='font-size:
+.0pt;line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'><span style='mso-element:
+field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"cseFSYyV","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":625,"uris":["http://zotero.org/users/local/DWdd4k1w/items/5RDB5DKM"],"itemData":{"id":625,"type":"article-journal","abstract":"Escherichia
+coli is generally used as model bacteria to define microbial cell factories for
+many products and to investigate regulation mechanisms. E. coli exhibits
+phospholipids, lipopolysaccharides, colanic acid, flagella and type I fimbriae
+on the outer membrane which is a self-protective barrier and closely related to
+cellular morphology, growth, phenotypes and stress adaptation. However, these
+outer membrane associated molecules could also lead to potential contamination
+and insecurity for fermentation products and consume lots of nutrients and
+energy sources. Therefore, understanding critical insights of these membrane
+associated molecules is necessary for building better microbial producers. Here
+the biosynthesis, function, influences, and current membrane engineering
+applications of these outer membrane associated molecules were reviewed from
+the perspective of synthetic biology, and the potential and effective
+engineering strategies on the outer membrane to improve fermentation features
+for microbial cell factories were
+suggested.","container-title":"Microbial Cell
+Factories","DOI":"10.1186/s12934-021-01565-8","ISSN":"1475-2859","issue":"1","journalAbbreviation":"Microbial
+Cell Factories","page":"73","source":"BioMed
+Central","title":"Insights into the structure of
+Escherichia coli outer membrane as the target for engineering microbial cell
+factories","URL":"https://doi.org/10.1186/s12934-021-01565-8","volume":"20","author":[{"family":"Wang","given":"Jianli"},{"family":"Ma","given":"Wenjian"},{"family":"Wang","given":"Xiaoyuan"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2021",3,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>6</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Wang, Ma, & Wang, 2021). EPS, flagella, and fimbria are nonessential
+structures; therefore, they are not present in all <i style='mso-bidi-font-style:
+normal'>E. coli'' strains</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"NU8TNhlB","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":625,"uris":["http://zotero.org/users/local/DWdd4k1w/items/5RDB5DKM"],"itemData":{"id":625,"type":"article-journal","abstract":"Escherichia
+coli is generally used as model bacteria to define microbial cell factories for
+many products and to investigate regulation mechanisms. E. coli exhibits
+phospholipids, lipopolysaccharides, colanic acid, flagella and type I fimbriae
+on the outer membrane which is a self-protective barrier and closely related to
+cellular morphology, growth, phenotypes and stress adaptation. However, these
+outer membrane associated molecules could also lead to potential contamination
+and insecurity for fermentation products and consume lots of nutrients and
+energy sources. Therefore, understanding critical insights of these membrane
+associated molecules is necessary for building better microbial producers. Here
+the biosynthesis, function, influences, and current membrane engineering
+applications of these outer membrane associated molecules were reviewed from
+the perspective of synthetic biology, and the potential and effective
+engineering strategies on the outer membrane to improve fermentation features
+for microbial cell factories were
+suggested.","container-title":"Microbial Cell
+Factories","DOI":"10.1186/s12934-021-01565-8","ISSN":"1475-2859","issue":"1","journalAbbreviation":"Microbial
+Cell
+Factories","page":"73","source":"BioMed
+Central","title":"Insights into the structure of
+Escherichia coli outer membrane as the target for engineering microbial cell
+factories","URL":"https://doi.org/10.1186/s12934-021-01565-8","volume":"20","author":[{"family":"Wang","given":"Jianli"},{"family":"Ma","given":"Wenjian"},{"family":"Wang","given":"Xiaoyuan"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2021",3,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>6</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Wang, Ma, & Wang, 2021). There are three important <span class=SpellE>Omps</span>:
+<span class=SpellE>OmpC</span>, <span class=SpellE>OmpF</span>, and OmpA</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"6h9AoQlU","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":625,"uris":["http://zotero.org/users/local/DWdd4k1w/items/5RDB5DKM"],"itemData":{"id":625,"type":"article-journal","abstract":"Escherichia
+coli is generally used as model bacteria to define microbial cell factories for
+many products and to investigate regulation mechanisms. E. coli exhibits
+phospholipids, lipopolysaccharides, colanic acid, flagella and type I fimbriae
+on the outer membrane which is a self-protective barrier and closely related to
+cellular morphology, growth, phenotypes and stress adaptation. However, these
+outer membrane associated molecules could also lead to potential contamination
+and insecurity for fermentation products and consume lots of nutrients and
+energy sources. Therefore, understanding critical insights of these membrane
+associated molecules is necessary for building better microbial producers. Here
+the biosynthesis, function, influences, and current membrane engineering
+applications of these outer membrane associated molecules were reviewed from
+the perspective of synthetic biology, and the potential and effective
+engineering strategies on the outer membrane to improve fermentation features
+for microbial cell factories were
+suggested.","container-title":"Microbial Cell
+Factories","DOI":"10.1186/s12934-021-01565-8","ISSN":"1475-2859","issue":"1","journalAbbreviation":"Microbial
+Cell
+Factories","page":"73","source":"BioMed
+Central","title":"Insights into the structure of
+Escherichia coli outer membrane as the target for engineering microbial cell
+factories","URL":"https://doi.org/10.1186/s12934-021-01565-8","volume":"20","author":[{"family":"Wang","given":"Jianli"},{"family":"Ma","given":"Wenjian"},{"family":"Wang","given":"Xiaoyuan"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2021",3,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>6</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Wang, Ma, & Wang, 2021). <span class=SpellE>OmpC</span> and <span
+class=SpellE>OmpF</span> regulate the entry of small molecule solutes into the
+cytoplasm while <span class=SpellE>OmpA</span> maintains <i style='mso-bidi-font-style:
+normal'>E. coli''’s cell surface integrity</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-begin'></span> ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"84c6pWvo","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":625,"uris":["http://zotero.org/users/local/DWdd4k1w/items/5RDB5DKM"],"itemData":{"id":625,"type":"article-journal","abstract":"Escherichia
+coli is generally used as model bacteria to define microbial cell factories for
+many products and to investigate regulation mechanisms. E. coli exhibits
+phospholipids, lipopolysaccharides, colanic acid, flagella and type I fimbriae
+on the outer membrane which is a self-protective barrier and closely related to
+cellular morphology, growth, phenotypes and stress adaptation. However, these
+outer membrane associated molecules could also lead to potential contamination
+and insecurity for fermentation products and consume lots of nutrients and
+energy sources. Therefore, understanding critical insights of these membrane
+associated molecules is necessary for building better microbial producers. Here
+the biosynthesis, function, influences, and current membrane engineering
+applications of these outer membrane associated molecules were reviewed from
+the perspective of synthetic biology, and the potential and effective
+engineering strategies on the outer membrane to improve fermentation features
+for microbial cell factories were suggested.","container-title":"Microbial
+Cell
+Factories","DOI":"10.1186/s12934-021-01565-8","ISSN":"1475-2859","issue":"1","journalAbbreviation":"Microbial
+Cell Factories","page":"73","source":"BioMed
+Central","title":"Insights into the structure of
+Escherichia coli outer membrane as the target for engineering microbial cell
+factories","URL":"https://doi.org/10.1186/s12934-021-01565-8","volume":"20","author":[{"family":"Wang","given":"Jianli"},{"family":"Ma","given":"Wenjian"},{"family":"Wang","given":"Xiaoyuan"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2021",3,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>6</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Wang, Ma, & Wang, 2021). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shapetype id="_x0000_t75" coordsize="21600,21600"
+o:spt="75" o:preferrelative="t" path="m@4@5l@4@11@9@11@9@5xe" filled="f"
+stroked="f"><v:stroke joinstyle="miter"/><v:formulas><v:f eqn="if lineDrawn pixelLineWidth 0"/><v:f eqn="sum @0 1 0"/><v:f eqn="sum 0 0 @1"/><v:f eqn="prod @2 1 2"/><v:f eqn="prod @3 21600 pixelWidth"/><v:f eqn="prod @3 21600 pixelHeight"/><v:f eqn="sum @0 0 1"/><v:f eqn="prod @6 1 2"/><v:f eqn="prod @7 21600 pixelWidth"/><v:f eqn="sum @8 21600 0"/><v:f eqn="prod @7 21600 pixelHeight"/><v:f eqn="sum @10 21600 0"/></v:formulas><v:path o:extrusionok="f" gradientshapeok="t" o:connecttype="rect"/><o:lock v:ext="edit" aspectratio="t"/></v:shapetype><v:shape id="image5.png" o:spid="_x0000_i1034" type="#_x0000_t75"
+style='width:4in;height:166.5pt;visibility:visible;mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image001.png" o:title=""/></v:shape><![endif]--><![if !vml]><img width=384 height=222
+src="Wiki%20Draft%20(1)_files/image002.gif" v:shapes="image5.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:10.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'>Figure X: The cell envelope of E. coli.
+The cell envelope is made of the inner membrane, peptidoglycan cell wall, and
+outer membrane. The inner membrane consists of a phospholipid (PL) bilayer. The
+peptidoglycan cell wall can be found in the periplasmic space between the IM
+and OM. It is made up of the </span><span lang=EN style='font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>NAG-NAM
+disaccharide, cross-linked by pentapeptide side chains. The peptidoglycan cell
+wall is connected to the OM via murein or Braun’s lipoprotein, <span
+class=SpellE>Lpp</span> (<span class=SpellE>coloured</span> dark blue). The OM
+consists of PLs in its inner leaflet, LPS molecules in its outer leaflet, and
+outer membrane proteins, <span class=SpellE>Omps</span> (<span class=SpellE>coloured</span>
+green). The outer membrane may also contain <span class=SpellE><span
+class=GramE>non essential</span></span> structures such as exopolysaccharides
+(EPS), flagella and type I fimbria.</span><span lang=EN style='font-size:8.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>LPS
+Structure<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN><a
+href="https://www.ocl-journal.org/articles/ocl/full_html/2020/01/ocl200025s/ocl200025s.html"><span
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'>https://www.ocl-journal.org/articles/ocl/full_html/2020/01/ocl200025s/ocl200025s.html</span></a></span><u><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'><o:p></o:p></span></u><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm'><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'>LPS are glycolipids comprised of three
+primary regions. The first is the lipid A region, which is typically made up of
+a bis-phosphorylated glucosamine disaccharide that carries fatty acids in ester
+and amide linkages. This region is connected to the second core oligosaccharide
+region via 2-keto-3 deoxy-<span class=SpellE>octulosonic</span> acid (<span
+class=SpellE>Kdo</span>). The third region is the O-chain, consisting of
+repeating oligosaccharide units and differs from one bacterium to another.<o:p></o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm'><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'>LPS Function<o:p></o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm;text-indent:36.0pt'><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'>LPS provides a
+permeability barrier that prevents the entry of harmful molecules. High density
+of saturated fatty acids <span class=GramE>cause</span> broadly and strong
+interaction with the acyl chain, and it synthesizes a low fluidity of the
+membrane bilayer. In addition, divalent cations between LPS molecules stabilize
+the high negativity of the membrane, which is caused by the presence of the
+phosphate group. <span class=SpellE>Polyionic</span> interaction within the
+outer membrane promotes LPS packing, and constructs LPS as a permeability
+barrier.<o:p></o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm;text-indent:36.0pt'><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'>LPS also contributes to
+impacting the virulence of the bacteria cell. LPS is more <span class=GramE>stable<span
+style='mso-spacerun:yes'>  </span>by</span> comparing with bacterial exotoxins,
+and is the primary<o:p></o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm;text-indent:36.0pt'><span lang=EN><a
+href="https://www.ncbi.nlm.nih.gov/books/NBK554414/#:~:text=The%20primary%20function%20of%20LPS,inhabitation%20in%20the%20gastrointestinal%20tract"><span
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'>https://www.ncbi.nlm.nih.gov/books/NBK554414/#:~:text=The%20primary%20function%20of%20LPS,inhabitation%20in%20the%20gastrointestinal%20tract</span></a></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>.
+</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;line-height:
+%;font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'><span style='mso-element:field-begin'></span><span
+style='mso-spacerun:yes'> </span>ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"zc9EP2pc","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":646,"uris":["http://zotero.org/users/local/DWdd4k1w/items/T75BDR5A"],"itemData":{"id":646,"type":"chapter","abstract":"Lipopolysaccharides
+(LPS) are important outer membrane components of gram-negative bacteria. They
+are large amphipathic glycoconjugates that typically consist of a lipid domain
+(hydrophobic) attached to a core oligosaccharide and a distal polysaccharide.
+These molecules are also known as lipogylcans due to the presence of lipid and
+sugar molecules. The lipopolysaccharides are composed of: 1. Lipid A:
+the hydrophobic domain, which is an endotoxin and the main virulence factor. 2.
+O-antigen, the repeating hydrophilic distal oligosaccharide. 3. The hydrophilic
+core polysaccharide. The lipid A component varies from one organism to another
+and is essential in imparting specific pathogenic attributes to the
+bacteria. Inherent to gram-negative bacteria, LPS provides integrity to
+the bacterial cell and a mechanism of interaction of the bacteria to other
+surfaces. Most bacterial LPS molecules are thermostable and generate a
+robust pro-inflammatory stimulus for the immune system in mammals. Since different
+types of LPS are present in different genera of gram-negative bacteria, LPS is
+used for serotyping gram-negative bacteria. More specifically, the
+O-antigen imparts serological distinction to the bacterial species. Also, the
+size and composition of LPS are highly dynamic among bacterial species. Due to
+its unique properties, LPS has gained considerable research focus to understand
+its complex structure, biogenesis, transport, and assembly. Besides, LPS is
+also a recognized biomarker due to its central role in host-pathogen
+interaction that facilitates the infection
+process.","call-number":"NBK554414","container-title":"StatPearls","event-place":"Treasure
+Island (FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID: 32119301","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Biochemistry,
+Lipopolysaccharide","URL":"http://www.ncbi.nlm.nih.gov/books/NBK554414/","author":[{"family":"Farhana","given":"Aisha"},{"family":"Khan","given":"Yusuf
+S."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>7</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><span
+style='mso-element:field-end'></span></span><![endif]--><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'>
+(Farhana)<o:p></o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm;text-indent:36.0pt'><span lang=EN><a
+href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091223/"><span
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091223/</span></a></span><u><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'></span></u><!--[if supportFields]><u><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'><span style='mso-element:field-begin'></span><span
+style='mso-spacerun:yes'> </span>ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"NPayMhvD","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":623,"uris":["http://zotero.org/users/local/DWdd4k1w/items/HUNH4ZWD"],"itemData":{"id":623,"type":"article-journal","abstract":"The
+cell envelope is the first line of defense between a bacterium and the
+world-at-large. Often, the initial steps that determine the outcome of chemical
+warfare, bacteriophage infections, and battles with other bacteria or the
+immune system greatly depend on the structure and composition of the bacterial
+cell surface. One of the most studied bacterial surface molecules is the glycolipid
+known as lipopolysaccharide (LPS), which is produced by most Gram-negative
+bacteria. Much of the initial attention LPS received in the early 1900s was
+owed to its ability to stimulate the immune system, for which the glycolipid
+was commonly known as endotoxin. It was later discovered that LPS also creates
+a permeability barrier at the cell surface and is a main contributor to the
+innate resistance that Gram-negative bacteria display against many
+antimicrobials. Not surprisingly, these important properties of LPS have driven
+a vast and still prolific body of literature for more than a hundred years. LPS
+research has also led to pioneering studies in bacterial envelope biogenesis
+and physiology, mostly using Escherichia coli and Salmonella as model systems.
+In this review, we will focus on the fundamental knowledge we have gained from
+studies of the complex structure of the LPS molecule and the biochemical
+pathways for its synthesis, as well as the transport of LPS across the
+bacterial envelope and its assembly at the cell
+surface.","container-title":"EcoSal
+Plus","DOI":"10.1128/ecosalplus.ESP-0001-2018","issue":"1","note":"publisher:
+American Society for Microbiology","source":"journals.asm.org
+(Atypon)","title":"Function and Biogenesis of
+Lipopolysaccharides","URL":"https://journals.asm.org/doi/10.1128/ecosalplus.ESP-0001-2018","volume":"8","author":[{"family":"Bertani","given":"Blake"},{"family":"Ruiz","given":"Natividad"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2018",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span></u><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>5</span></sup><!--[if supportFields]><u><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC;background:white;
+mso-highlight:white'><span style='mso-element:field-end'></span></span></u><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";background:white;mso-highlight:white'><o:p></o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm;text-indent:36.0pt'><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'><o:p> </o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm;text-indent:36.0pt'><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";background:white;mso-highlight:white'><o:p> </o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm'><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'><o:p> </o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm'><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'><o:p> </o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm'><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'><o:p> </o:p></span><p class=MsoNormal style='margin-top:12.0pt;margin-right:0cm;margin-bottom:
+.0pt;margin-left:0cm'><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+background:white;mso-highlight:white'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.0 LPS synthesis<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>The
+LPS biosynthesis pathway is crucial for the structural makeup of gram-negative
+bacteria’s outer membrane</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"duQKHHWi","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":638,"uris":["http://zotero.org/users/local/DWdd4k1w/items/ZRPN7M3N"],"itemData":{"id":638,"type":"article-journal","abstract":"Lipopolysaccharide
+that constitutes the outer leaflet of the outer membrane of most Gram-negative
+bacteria is referred to as an endotoxin. It is comprised of a hydrophilic polysaccharide
+and a hydrophobic component referred to as lipid A. Lipid A is responsible for
+the major bioactivity of endotoxin, and is recognized by immune cells as a
+pathogen-associated molecule. Most enzymes and genes coding for proteins
+responsible for the biosynthesis and export of lipopolysaccharide in
+Escherichia coli have been identified, and they are shared by most
+Gram-negative bacteria based on genetic information. The detailed structure of
+lipopolysaccharide differs from one bacterium to another, consistent with the
+recent discovery of additional enzymes and gene products that can modify the
+basic structure of lipopolysaccharide in some bacteria, especially pathogens.
+These modifications are not required for survival, but are tightly regulated in
+the cell and closely related to the virulence of bacteria. In this review we
+discuss recent studies of the biosynthesis and export of lipopolysaccharide,
+and the relationship between the structure of lipopolysaccharide and the
+virulence of bacteria.","container-title":"Progress in
+Lipid
+Research","DOI":"10.1016/j.plipres.2009.06.002","ISSN":"0163-7827","issue":"2","journalAbbreviation":"Progress
+in Lipid Research","language":"en","page":"97-107","source":"ScienceDirect","title":"Lipopolysaccharide:
+Biosynthetic pathway and structure
+modification","title-short":"Lipopolysaccharide","URL":"https://www.sciencedirect.com/science/article/pii/S0163782709000526","volume":"49","author":[{"family":"Wang","given":"Xiaoyuan"},{"family":"Quinn","given":"Peter
+J."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",4,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>8</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Wang & Quinn, 2010). Reflected
+in the structure of LPS, its synthesis is dependent on the formation of its
+three regions: Lipid A, the core oligosaccharide, and the O-antigen. LPS
+synthesis occurs within the cytoplasm along the inner membrane surface.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.1 Lipid A synthesis<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>The
+LPS biosynthesis starts with the conserved pathway of lipid A synthesis as
+displayed in <b style='mso-bidi-font-weight:normal'>Figure X '''</span><!--[if supportFields]><b
+style='mso-bidi-font-weight:normal'><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span><span
+style='mso-spacerun:yes'> </span>ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"2I1GZm5a","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":642,"uris":["http://zotero.org/users/local/DWdd4k1w/items/WA5WMMWJ"],"itemData":{"id":642,"type":"article-journal","abstract":"Lipopolysaccharide
+molecules represent a unique family of glycolipids based on a highly conserved
+lipid moiety known as lipid A. These molecules are produced by most
+gram-negative bacteria, in which they play important roles in the integrity of
+the outer-membrane permeability barrier and participate extensively in
+host?pathogen interplay. Few bacteria contain lipopolysaccharide molecules
+composed only of lipid A. In most forms, lipid A is glycosylated by addition of
+the core oligosaccharide that, in some bacteria, provides an attachment site
+for a long-chain O-antigenic polysaccharide. The complexity of
+lipopolysaccharide structures is reflected in the processes used for their
+biosynthesis and export. Rapid growth and cell division depend on the bacterial
+cell's capacity to synthesize and export lipopolysaccharide efficiently and in
+large amounts. We review recent advances in those processes, emphasizing the
+reactions that are essential for
+viability.","container-title":"Annual Review of
+Biochemistry","DOI":"10.1146/annurev-biochem-060713-035600","ISSN":"0066-4154","issue":"1","journalAbbreviation":"Annu.
+Rev. Biochem.","note":"publisher: Annual
+Reviews","page":"99-128","title":"Biosynthesis
+and Export of Bacterial
+Lipopolysaccharides","URL":"https://doi.org/10.1146/annurev-biochem-060713-035600","volume":"83","author":[{"family":"Whitfield","given":"Chris"},{"family":"Trent","given":"M.
+Stephen"}],"accessed":{"date-parts":[["2023",2,2]]},"issued":{"date-parts":[["2014",6,2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span>'''<![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>9</span></sup><!--[if supportFields]><b
+style='mso-bidi-font-weight:normal'><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-end'></span></span>'''<![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Whitfield & Trent, 2014). This
+pathway begins with a UDP-N-acetylglucosamine (UDP-<span class=SpellE>GlcNAc</span>)
+molecule</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"TH4VaFYV","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":638,"uris":["http://zotero.org/users/local/DWdd4k1w/items/ZRPN7M3N"],"itemData":{"id":638,"type":"article-journal","abstract":"Lipopolysaccharide
+that constitutes the outer leaflet of the outer membrane of most Gram-negative
+bacteria is referred to as an endotoxin. It is comprised of a hydrophilic
+polysaccharide and a hydrophobic component referred to as lipid A. Lipid A is
+responsible for the major bioactivity of endotoxin, and is recognized by immune
+cells as a pathogen-associated molecule. Most enzymes and genes coding for
+proteins responsible for the biosynthesis and export of lipopolysaccharide in
+Escherichia coli have been identified, and they are shared by most
+Gram-negative bacteria based on genetic information. The detailed structure of
+lipopolysaccharide differs from one bacterium to another, consistent with the
+recent discovery of additional enzymes and gene products that can modify the
+basic structure of lipopolysaccharide in some bacteria, especially pathogens.
+These modifications are not required for survival, but are tightly regulated in
+the cell and closely related to the virulence of bacteria. In this review we
+discuss recent studies of the biosynthesis and export of lipopolysaccharide,
+and the relationship between the structure of lipopolysaccharide and the
+virulence of bacteria.","container-title":"Progress in
+Lipid Research","DOI":"10.1016/j.plipres.2009.06.002","ISSN":"0163-7827","issue":"2","journalAbbreviation":"Progress
+in Lipid
+Research","language":"en","page":"97-107","source":"ScienceDirect","title":"Lipopolysaccharide:
+Biosynthetic pathway and structure
+modification","title-short":"Lipopolysaccharide","URL":"https://www.sciencedirect.com/science/article/pii/S0163782709000526","volume":"49","author":[{"family":"Wang","given":"Xiaoyuan"},{"family":"Quinn","given":"Peter
+J."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",4,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>8</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Wang & Quinn, 2010). Lipid A
+synthesis involves the addition of hydrophobic fatty acid chains to UDP-<span
+class=SpellE>GlcNAc</span> catalyzed by <span class=SpellE>LpxA</span>, <span
+class=SpellE>LpxC</span> and <span class=SpellE>LpxD</span>, forming
+UDP-diacyl-<span class=SpellE>GlcN</span>. <span style='color:#212121;
+background:white;mso-highlight:white'>Although the biosynthesis begins with the
+acylation of UDP-<span class=SpellE>GlcNAc</span>, catalyzed by <span
+class=SpellE>LpxA</span>, this reaction is thermodynamically unfavourable</span></span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#212121;background:white;
+mso-highlight:white'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"8vx6d2Gc","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"10","noteIndex":0},"citationItems":[{"id":632,"uris":["http://zotero.org/users/local/DWdd4k1w/items/W6EZIQHQ"],"itemData":{"id":632,"type":"article-journal","abstract":"Multi-drug
+resistant (MDR), pathogenic Gram-negative bacteria pose a serious health
+threat, and novel antibiotic targets must be identified to combat MDR infections.
+One promising target is the zinc-dependent metalloamidase
+UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), which
+catalyzes the committed step of lipid A (endotoxin) biosynthesis. LpxC is an
+essential, single copy gene that is conserved in virtually all Gram-negative
+bacteria. LpxC structures, revealed by NMR and X-ray crystallography,
+demonstrate that LpxC adopts a novel ‘β-α-α-β sandwich’
+fold and encapsulates the acyl chain of the substrate with a unique hydrophobic
+passage. Kinetic analysis revealed that LpxC functions by a general acid-base
+mechanism, with a glutamate serving as the general base.<span
+style='mso-spacerun:yes'>   </span>Many potent LpxC inhibitors have been
+identified, and most contain a hydroxamate group targeting the catalytic zinc
+ion. Although early LpxC-inhibitors were either narrow-spectrum antibiotics or
+broad-spectrum in vitro LpxC inhibitors with limited antibiotic properties, the
+recently discovered compound CHIR-090 is a powerful antibiotic that controls
+the growth of Escherichia coli and Pseudomonas aeruginosa, with an efficacy
+rivaling that of the FDA-approved antibiotic ciprofloxacin. CHIR-090 inhibits a
+wide range of LpxC enzymes with sub-nanomolar affinity in vitro, and is a
+two-step, slow, tight-binding inhibitor of Aquifex aeolicus and E. coli LpxC.
+The success of CHIR-090 suggests that potent LpxCtargeting antibiotics may be
+developed to control a broad range of Gram-negative
+bacteria.","container-title":"Current Pharmaceutical
+Biotechnology","issue":"1","language":"en","page":"9-15","source":"www.eurekaselect.com","title":"Mechanism
+and Inhibition of LpxC: An Essential Zinc-Dependent Deacetylase of Bacterial
+Lipid A Synthesis","title-short":"Mechanism and Inhibition
+of
+LpxC","URL":"https://www.eurekaselect.com/article/11296","volume":"9","author":[{"family":"Zhou","given":"Pei"},{"family":"Barb","given":"Adam
+W."}],"accessed":{"date-parts":[["2023",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>10</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#212121;background:white;
+mso-highlight:white'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#212121;background:white;
+mso-highlight:white'> (Barb & Zhou, 2008). Thus, the first committed step
+of lipid A biosynthesis is the deacetylation reaction catalyzed by <span
+class=SpellE>LpxC</span></span><span lang=EN style='font-size:15.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman";color:#212121;background:white;mso-highlight:white'>. </span><span
+class=SpellE><span lang=EN style='font-size:12.0pt;line-height:115%;font-family:
+"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>LpxC</span></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> is a crucial enzyme as it catalyzes
+the non-reversible step in lipid A synthesis which is the deacetylation of UDP-3-O-(acyl)-<span
+class=SpellE>GlcNAc</span>. <span class=SpellE>LpxC</span> also has a unique
+sequence compared to other deacetylases and plays a regulatory role in lipid A
+biosynthesis, which makes it an attractive target for antibiotic development</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"8KyB55he","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":638,"uris":["http://zotero.org/users/local/DWdd4k1w/items/ZRPN7M3N"],"itemData":{"id":638,"type":"article-journal","abstract":"Lipopolysaccharide
+that constitutes the outer leaflet of the outer membrane of most Gram-negative
+bacteria is referred to as an endotoxin. It is comprised of a hydrophilic
+polysaccharide and a hydrophobic component referred to as lipid A. Lipid A is
+responsible for the major bioactivity of endotoxin, and is recognized by immune
+cells as a pathogen-associated molecule. Most enzymes and genes coding for
+proteins responsible for the biosynthesis and export of lipopolysaccharide in
+Escherichia coli have been identified, and they are shared by most
+Gram-negative bacteria based on genetic information. The detailed structure of
+lipopolysaccharide differs from one bacterium to another, consistent with the
+recent discovery of additional enzymes and gene products that can modify the
+basic structure of lipopolysaccharide in some bacteria, especially pathogens.
+These modifications are not required for survival, but are tightly regulated in
+the cell and closely related to the virulence of bacteria. In this review we
+discuss recent studies of the biosynthesis and export of lipopolysaccharide,
+and the relationship between the structure of lipopolysaccharide and the
+virulence of bacteria.","container-title":"Progress in
+Lipid Research","DOI":"10.1016/j.plipres.2009.06.002","ISSN":"0163-7827","issue":"2","journalAbbreviation":"Progress
+in Lipid
+Research","language":"en","page":"97-107","source":"ScienceDirect","title":"Lipopolysaccharide:
+Biosynthetic pathway and structure
+modification","title-short":"Lipopolysaccharide","URL":"https://www.sciencedirect.com/science/article/pii/S0163782709000526","volume":"49","author":[{"family":"Wang","given":"Xiaoyuan"},{"family":"Quinn","given":"Peter
+J."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",4,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>8</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Wang & Quinn, 2010). Following
+<span class=SpellE>LpxD</span> action, UDP-diacyl-<span class=SpellE>GlcN</span>
+undergoes a series of reactions catalyzed by three other enzymes, <span
+class=SpellE>LpxH</span>, <span class=SpellE>LpxB</span> and <span
+class=SpellE>LpxK</span>, to compose lipid IV<sub>A</sub>.<span
+style='mso-spacerun:yes'>  </span>Two <span class=SpellE>Kdo</span> molecules
+are added to Lipid IV<sub>A</sub>, catalyzed by the bifunctional <span
+class=SpellE>KdtA</span>. Kdo<sub>2</sub>-LipidIV<sub>A</sub> is further
+modified with acyltransferases, <span class=SpellE>LpxL</span> and <span
+class=SpellE>LpxM</span>, to form Kdo<sub>2</sub>-Lipid A.<span
+style='mso-spacerun:yes'>  </span>Kdo<sub>2</sub>-Lipid A is the active form
+that is used for the addition of core oligosaccharides and overall assembly of
+LPS.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.2 Core Oligosaccharides
+synthesis/addition<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>The
+core oligosaccharides are added to lipid A on the cytoplasmic surface of the
+inner membrane through membrane-bound glycosyltransferases and nucleotide sugar
+donors</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"Hvjl9LDm","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":638,"uris":["http://zotero.org/users/local/DWdd4k1w/items/ZRPN7M3N"],"itemData":{"id":638,"type":"article-journal","abstract":"Lipopolysaccharide
+that constitutes the outer leaflet of the outer membrane of most Gram-negative
+bacteria is referred to as an endotoxin. It is comprised of a hydrophilic
+polysaccharide and a hydrophobic component referred to as lipid A. Lipid A is
+responsible for the major bioactivity of endotoxin, and is recognized by immune
+cells as a pathogen-associated molecule. Most enzymes and genes coding for
+proteins responsible for the biosynthesis and export of lipopolysaccharide in
+Escherichia coli have been identified, and they are shared by most Gram-negative
+bacteria based on genetic information. The detailed structure of
+lipopolysaccharide differs from one bacterium to another, consistent with the
+recent discovery of additional enzymes and gene products that can modify the
+basic structure of lipopolysaccharide in some bacteria, especially pathogens.
+These modifications are not required for survival, but are tightly regulated in
+the cell and closely related to the virulence of bacteria. In this review we
+discuss recent studies of the biosynthesis and export of lipopolysaccharide,
+and the relationship between the structure of lipopolysaccharide and the
+virulence of bacteria.","container-title":"Progress in
+Lipid Research","DOI":"10.1016/j.plipres.2009.06.002","ISSN":"0163-7827","issue":"2","journalAbbreviation":"Progress
+in Lipid
+Research","language":"en","page":"97-107","source":"ScienceDirect","title":"Lipopolysaccharide:
+Biosynthetic pathway and structure modification","title-short":"Lipopolysaccharide","URL":"https://www.sciencedirect.com/science/article/pii/S0163782709000526","volume":"49","author":[{"family":"Wang","given":"Xiaoyuan"},{"family":"Quinn","given":"Peter
+J."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",4,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>8</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Wang & Quinn, 2010). The core
+oligosaccharides have two components: the inner core and the outer core. The
+inner core is the conserved region of the core oligosaccharides and includes <span
+class=SpellE>Kdo</span> molecules as well as the L-<span class=SpellE>glycero</span>-D-<span
+class=SpellE>manno</span>-heptose molecule (Hep)</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"9jd2Utu1","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":642,"uris":["http://zotero.org/users/local/DWdd4k1w/items/WA5WMMWJ"],"itemData":{"id":642,"type":"article-journal","abstract":"Lipopolysaccharide
+molecules represent a unique family of glycolipids based on a highly conserved
+lipid moiety known as lipid A. These molecules are produced by most
+gram-negative bacteria, in which they play important roles in the integrity of
+the outer-membrane permeability barrier and participate extensively in
+host?pathogen interplay. Few bacteria contain lipopolysaccharide molecules
+composed only of lipid A. In most forms, lipid A is glycosylated by addition of
+the core oligosaccharide that, in some bacteria, provides an attachment site
+for a long-chain O-antigenic polysaccharide. The complexity of lipopolysaccharide
+structures is reflected in the processes used for their biosynthesis and
+export. Rapid growth and cell division depend on the bacterial cell's capacity
+to synthesize and export lipopolysaccharide efficiently and in large amounts.
+We review recent advances in those processes, emphasizing the reactions that
+are essential for viability.","container-title":"Annual
+Review of
+Biochemistry","DOI":"10.1146/annurev-biochem-060713-035600","ISSN":"0066-4154","issue":"1","journalAbbreviation":"Annu.
+Rev. Biochem.","note":"publisher: Annual
+Reviews","page":"99-128","title":"Biosynthesis
+and Export of Bacterial
+Lipopolysaccharides","URL":"https://doi.org/10.1146/annurev-biochem-060713-035600","volume":"83","author":[{"family":"Whitfield","given":"Chris"},{"family":"Trent","given":"M.
+Stephen"}],"accessed":{"date-parts":[["2023",2,2]]},"issued":{"date-parts":[["2014",6,2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>9</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Whitfield & Trent, 2014). The
+formation and attachment of Hep are mediated by enzymes synthesized by the <span
+class=SpellE><i style='mso-bidi-font-style:normal'>gmhD''</span><i
+style='mso-bidi-font-style:normal'>''operon. On the other hand, the outer
+core region is less conserved. The outer core oligosaccharides are synthesized
+by gene products of the <span class=SpellE>waaQ</span> operons.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.3 O-antigen addition<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>The
+O-antigen polymers are added to the outer core oligosaccharides through
+glycosyltransferases and nucleotide sugar donors</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"TLflZagS","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":638,"uris":["http://zotero.org/users/local/DWdd4k1w/items/ZRPN7M3N"],"itemData":{"id":638,"type":"article-journal","abstract":"Lipopolysaccharide
+that constitutes the outer leaflet of the outer membrane of most Gram-negative
+bacteria is referred to as an endotoxin. It is comprised of a hydrophilic
+polysaccharide and a hydrophobic component referred to as lipid A. Lipid A is
+responsible for the major bioactivity of endotoxin, and is recognized by immune
+cells as a pathogen-associated molecule. Most enzymes and genes coding for
+proteins responsible for the biosynthesis and export of lipopolysaccharide in
+Escherichia coli have been identified, and they are shared by most
+Gram-negative bacteria based on genetic information. The detailed structure of
+lipopolysaccharide differs from one bacterium to another, consistent with the
+recent discovery of additional enzymes and gene products that can modify the
+basic structure of lipopolysaccharide in some bacteria, especially pathogens.
+These modifications are not required for survival, but are tightly regulated in
+the cell and closely related to the virulence of bacteria. In this review we
+discuss recent studies of the biosynthesis and export of lipopolysaccharide,
+and the relationship between the structure of lipopolysaccharide and the
+virulence of bacteria.","container-title":"Progress in Lipid
+Research","DOI":"10.1016/j.plipres.2009.06.002","ISSN":"0163-7827","issue":"2","journalAbbreviation":"Progress
+in Lipid Research","language":"en","page":"97-107","source":"ScienceDirect","title":"Lipopolysaccharide:
+Biosynthetic pathway and structure modification","title-short":"Lipopolysaccharide","URL":"https://www.sciencedirect.com/science/article/pii/S0163782709000526","volume":"49","author":[{"family":"Wang","given":"Xiaoyuan"},{"family":"Quinn","given":"Peter
+J."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2010",4,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>8</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Wang & Quinn, 2010). The <span
+class=SpellE><i style='mso-bidi-font-style:normal'>rfb''</span> gene cluster
+enzyme derivatives contribute to O-antigen diversity through the creation of
+enzymes for varying sugar-nucleotide precursors. The <span class=SpellE><i
+style='mso-bidi-font-style:normal'>rfb''</span> operon also synthesizes
+glycosyltransferases, polymerases, and proteins needed for O-antigen transport
+through the inner membrane.<o:p></o:p></span><p class=MsoNormal style='margin-bottom:12.0pt'><span lang=EN style='font-size:
+.0pt;line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-spacerun:yes'> </span><span
+style='mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image1.png" o:spid="_x0000_i1033"
+type="#_x0000_t75" style='width:468pt;height:328pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image003.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=624 height=437
+src="Wiki%20Draft%20(1)_files/image004.gif" v:shapes="image1.png"><![endif]></span><o:p></o:p></span><p class=MsoNormal style='margin-bottom:12.0pt'><b style='mso-bidi-font-weight:
+normal'><span lang=EN style='font-size:12.0pt;line-height:115%;font-family:
+"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Figure X</span>'''<span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>: Kdo2-Lipid A synthesis, the first
+part of LPS synthesis. Kdo2-Lipid A synthesis involves the first committed step
+in LPS synthesis, catalyzed by <span class=SpellE>LpxC</span>, which is the
+deacetylation of UDP-3-O-(acyl)-<span class=SpellE>GlcNAc</span> (red box)</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"IUPlTF6N","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":636,"uris":["http://zotero.org/users/local/DWdd4k1w/items/KN5AUCNU"],"itemData":{"id":636,"type":"article-journal","abstract":"UDP-N-acetylglucosamine
+(UDP-GlcNAc) acyltransferase (LpxA) catalyzes the first step of lipid A
+biosynthesis, the reversible transfer of the R-3-hydroxyacyl chain from
+R-3-hydroxyacyl acyl carrier protein to the glucosamine 3-OH group of
+UDP-GlcNAc. Escherichia coli LpxA is highly selective for R-3-hydroxymyristate.
+The crystal structure of the E. coli LpxA homotrimer, determined previously in
+the absence of lipid substrates or products, revealed that LpxA contains an
+unusual, left-handed parallel β-helix fold. We have now solved the crystal
+structures of E. coli LpxA with the bound product
+UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc at a resolution of 1.74 Å and with bound
+UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc at 1.85 Å. The structures of these
+complexes are consistent with the catalytic mechanism deduced by mutagenesis
+and with a recent 3.0-Å structure of LpxA with bound UDP-GlcNAc. Our structures
+show how LpxA selects for 14-carbon R-3-hydroxyacyl chains and reveal two modes
+of UDP binding.","container-title":"Proceedings of the
+National Academy of
+Sciences","DOI":"10.1073/pnas.0705833104","issue":"34","note":"publisher:
+Proceedings of the National Academy of
+Sciences","page":"13543-13550","source":"pnas.org
+(Atypon)","title":"Structural basis for the acyl chain
+selectivity and mechanism of UDP-N-acetylglucosamine
+acyltransferase","URL":"https://www.pnas.org/doi/full/10.1073/pnas.0705833104","volume":"104","author":[{"family":"Williams","given":"Allison
+H."},{"family":"Raetz","given":"Christian
+R. H."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2007",8,21]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>11</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Williams & <span class=SpellE>Raetz</span>,
+). <o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN>LPS
+transport <o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN>LPS transport begins with the movement of LPS
+from the inner membrane to the outer membrane and involves <span class=SpellE>MsbA</span>
+translocation (<span class=SpellE>Sperandeo</span> et al., 2017). <span
+class=SpellE>MsbA</span><span class=SpellE>flippase</span> catalyzes the
+flipping of the Lipid A core moiety across the inner membrane. Following
+complete synthesis, the movement of the mature LPS molecule to the cell surface
+is assisted by the LPT molecular machine. Broadly, the transport of LPS from
+the inner membrane to the outer membrane can be divided into three key steps:
+LPS detachment from the inner membrane, LPS transport across the periplasm, and
+LPS insertion and assembly in the outer membrane at the cell surface (<span
+class=SpellE>Sperandeo</span> et al., 2017). </span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN>Regulation
+<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>LPS
+assembly begins on the internal surface of the <span class=GramE><i
+style='mso-bidi-font-style:normal'>E.coli''</span> membrane. The rate of LPS
+assembly is controlled by <span class=SpellE>LpxC</span>. Prior to the
+completion of LPS biosynthesis, the lipid undergoes further modifications when
+it is flipped to the external surface of the inner membrane. Following
+synthesis completion, LPS is transported to the outer membrane’s external
+surface via a protein bridge that connects both the inner and outer membranes</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"vnUtrtYB","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology,
+Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020). </span><span
+lang=EN style='background:white;mso-highlight:white'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Feedback
+inhibition is a key cellular control mechanism where the activity of a key
+enzyme within a pathway is inhibited by that same enzyme's <span class=GramE>end
+product</span>(s). This control mechanism is essential in controlling and
+regulating LPS biosynthesis. It is currently unknown but it has been suspected
+that LPS or a precursor of LPS is the feedback signal responsible for LPS
+regulation</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION {"citationID":"EPagjeP8","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology,
+Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020).<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image4.png" o:spid="_x0000_i1032"
+type="#_x0000_t75" style='width:467.5pt;height:200.5pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image005.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=623 height=267
+src="Wiki%20Draft%20(1)_files/image006.gif" v:shapes="image4.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span>There are 3 scenarios involving LPS
+biosynthesis that will be discussed:<span style='mso-spacerun:yes'>
+</span>typical LPS biosynthesis, LPS excess, and LPS deficiency. <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Beginning
+with normal LPS synthesis that takes place within the cell cytoplasm, the
+enzyme <span class=SpellE>LpxC</span> controls the biosynthesis of LPS while
+utilizing precursors located in the <span class=GramE>cytoplasm .</span>
+Following biosynthesis, the immature LPS is flipped onto the external surface
+of the inner membrane and is then transported to the outer membrane. The <span
+class=SpellE>FtsH</span> enzyme, guided by interactions with <span
+class=SpellE>LapB</span>, degrades <span class=SpellE>LpxC</span> which
+disrupts LPS biosynthesis</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"OZBbxks7","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology,
+Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020). However, <span
+class=SpellE>Clairefeuille</span> and colleagues show that a protein, <span
+class=SpellE>PbgA</span>, inhibits <span class=SpellE>LapB-FtsH</span> activity
+to promote LPS biosynthesis (2020). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image8.png" o:spid="_x0000_i1031"
+type="#_x0000_t75" style='width:465.5pt;height:326.5pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image007.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=621 height=435
+src="Wiki%20Draft%20(1)_files/image008.gif" v:shapes="image8.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Figure
+_. LPS synthesis and degradation of <span class=SpellE>LpxC</span>. The enzyme <span
+class=SpellE>LpxC</span> controls the biosynthesis of LPS, utilizing precursors
+located within the <span class=GramE><i style='mso-bidi-font-style:normal'>E.coli''</span><i
+style='mso-bidi-font-style:normal'>''cell cytoplasm. After being flipped to
+the external surface of the inner membrane through an ABC transporter, the
+mature LPS is transported to the outer membrane using LPT machinery. The enzyme
+<span class=SpellE>FtsH</span>, aided by interactions with the protein <span
+class=SpellE>LapB</span>, degrades <span class=SpellE>LpxC</span>. <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image10.png" o:spid="_x0000_i1030"
+type="#_x0000_t75" style='width:467.5pt;height:336pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image009.png" o:title=""
+cropright="494f"/></v:shape><![endif]--><![if !vml]><img border=0 width=623 height=448
+src="Wiki%20Draft%20(1)_files/image010.gif" v:shapes="image10.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Figure
+_. Inhibition of <span class=SpellE>FtsH-LapB</span> activity. <span
+class=SpellE>PbgA</span> is a protein that inhibits the actions of <span
+class=SpellE>FtsH-LapB</span> to promote LPS biosynthesis. <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Next,
+when LPS is being synthesized in excessive amounts, it will accumulate on the
+external surface of the inner membrane and bind to PbgA</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"8hpU9wVs","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology, Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020). Thereby, <span
+class=SpellE>PbgA</span> will lessen its control on the <span class=SpellE>LapB-FtsH</span>
+complex activity, allowing for the degradation of <span class=SpellE>LpxC</span>
+to restore normal LPS levels.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image9.png" o:spid="_x0000_i1029"
+type="#_x0000_t75" style='width:468pt;height:319.5pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image011.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=624 height=426
+src="Wiki%20Draft%20(1)_files/image012.gif" v:shapes="image9.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Figure
+_. LPS excess. When LPS is being synthesized in excess, it will begin to
+accumulate on the external surface of the inner membrane and bind to <span
+class=SpellE>PbgA</span>. Bound to LPS, the protein will relax its inhibitory
+control on <span class=SpellE>FtsH-LapB</span> to promote <span class=SpellE>LpxC</span>
+degradation and therefore, restores normal LPS levels. <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>There
+is a truncation mutation of <span class=SpellE>PbgA</span> that leads to the
+depletion of LPS. This is most likely because the mutant fails to strongly
+inhibit the <span class=SpellE>LapB-FtsH</span> interaction that degrades <span
+class=SpellE>LpxC</span> and thereby, promotes <span class=SpellE>LpxC</span>
+degradation</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"KLS9MM71","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia
+coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology,
+Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020). PLs then fill in
+the gaps that are left by the LPS in the outer membrane, enabling greasy
+antibiotics and detergents to penetrate local PL bilayers, and large soluble
+compounds to leak through transient boundary defects where LPS and the PL
+phases meet</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"xpZv7lIL","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":617,"uris":["http://zotero.org/users/local/DWdd4k1w/items/FDC6F69M"],"itemData":{"id":617,"type":"article-journal","abstract":"PbgA
+proteins controls lipopolysaccharide synthesis in Escherichia coli.","container-title":"Nature","DOI":"10.1038/d41586-020-02256-x","issue":"7821","language":"en","license":"2021
+Nature","note":"Bandiera_abtest: a\nCg_type: News And
+Views\nnumber: 7821\npublisher: Nature Publishing Group\nSubject_term:
+Structural biology, Microbiology","page":"348-349","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of a lipopolysaccharide regulator reveals a road to new
+antibiotics","URL":"http://www.nature.com/articles/d41586-020-02256-x","volume":"584","author":[{"family":"Bishop","given":"Russell
+E."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>2</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Bishop, 2020).<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image7.png" o:spid="_x0000_i1028"
+type="#_x0000_t75" style='width:455.5pt;height:319.5pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image013.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=607 height=426
+src="Wiki%20Draft%20(1)_files/image014.gif" v:shapes="image7.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal style='margin-bottom:12.0pt'><span lang=EN style='font-size:
+.0pt;line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-spacerun:yes'> </span>Figure_. <span
+class=SpellE>PbgA</span> truncation mutation leads to LPS depletion. A
+depletion of LPS occurs when there is a <span class=SpellE>PbgA</span>
+truncation mutation, most likely due to the mutant failing to inhibit <span
+class=SpellE>FtsH-LapB</span> strongly enough. Therefore, PLs will attempt to
+fill in the gaps left by the depletion of LPS in the outer membrane. This
+enables greasy antibiotics and detergents to penetrate as well as large soluble
+compounds to leak through. <o:p></o:p></span><p class=MsoNormal><span lang=EN><a
+href="https://journals.asm.org/doi/10.1128/ecosalplus.ESP-0001-2018"><span
+style='font-size:13.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC'>https://journals.asm.org/doi/10.1128/ecosalplus.ESP-0001-2018</span></a></span><u><span
+lang=EN style='font-size:13.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman";color:#1155CC'><o:p></o:p></span></u><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X: <span class=SpellE>PbgA</span><o:p></o:p></span>'''<p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.1 <span class=SpellE>PbgA</span>
+Structure <o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span class=SpellE><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'>PbgA</span></span><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'>, also known as <span class=SpellE>YejM</span>, is an
+essential protein in <i style='mso-bidi-font-style:normal'>E. coli'' that is
+required for regulating LPS synthesis and maintaining membrane homeostasis</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"UlToei0B","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":628,"uris":["http://zotero.org/users/local/DWdd4k1w/items/K232PHWH"],"itemData":{"id":628,"type":"article-journal","abstract":"Gram-negative
+bacteria produce an asymmetric outer membrane (OM) that is particularly
+impermeant to many antibiotics and characterized by lipopolysaccharide (LPS)
+exclusively at the cell surface. LPS biogenesis remains an ideal target for
+therapeutic intervention, as disruption could kill bacteria or increase
+sensitivity to existing antibiotics. While it has been known that LPS synthesis
+is regulated by proteolytic control of LpxC, the enzyme that catalyzes the
+first committed step of LPS synthesis, it remains unknown which signals direct
+this regulation. New details have been revealed during study of a cryptic
+essential inner membrane protein, YejM. Multiple functions have been proposed
+over the years for YejM, including a controversial hypothesis that it
+transports cardiolipin from the inner membrane to the OM. Strong evidence now
+indicates that YejM senses LPS in the periplasm and directs proteolytic
+regulation. Here, we discuss the standing literature of YejM and highlight
+exciting new insights into cell envelope
+maintenance.","container-title":"mBio","DOI":"10.1128/mBio.02624-20","issue":"6","note":"publisher:
+American Society for
+Microbiology","page":"e02624-20","source":"journals.asm.org
+(Atypon)","title":"Restoring Balance to the Outer Membrane:
+YejM’s Role in LPS Regulation","title-short":"Restoring
+Balance to the Outer
+Membrane","URL":"https://journals.asm.org/doi/10.1128/mBio.02624-20","volume":"11","author":[{"family":"Simpson","given":"Brent
+W."},{"family":"Douglass","given":"Martin
+V."},{"family":"Trent","given":"M.
+Stephen"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",12,15]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>12</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Simpson et al., 2020). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>As
+shown in Figure X, <span class=SpellE>PbgA</span> is an inner membrane protein
+with a five-transmembrane-domain N terminus (residues 1-190) that is essential
+for growth and a nonessential C-terminal periplasmic domain (residues 191-586).
+Nonsense mutations that cause truncations in the periplasmic domain in <span
+class=SpellE>PbgA</span> cause phenotypes consistent with defects in outer membrane
+assembly, including reduced LPS/PL ratio, vancomycin sensitivity, temperature
+sensitivity, and leakage of periplasmic proteins</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"KISnKvoZ","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":619,"uris":["http://zotero.org/users/local/DWdd4k1w/items/HWCQ9FUI"],"itemData":{"id":619,"type":"article-journal","abstract":"Gram-negative
+bacteria are surrounded by a complex cell envelope that includes two membranes.
+The outer membrane prevents many drugs from entering these cells and is thus a
+major determinant of their intrinsic antibiotic resistance. This barrier
+function is imparted by the asymmetric architecture of the membrane with
+lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner leaflet.
+The LPS and phospholipid synthesis pathways share an intermediate. Proper
+membrane biogenesis therefore requires that the flux through each pathway be
+balanced. In Escherichia coli, a major control point in establishing this
+balance is the committed step of LPS synthesis mediated by LpxC. Levels of this
+enzyme are controlled through its degradation by the inner membrane protease
+FtsH and its presumed adapter protein LapB (YciM). How turnover of LpxC is
+controlled has remained unclear for many years. Here, we demonstrate that the
+essential protein of unknown function YejM (PbgA) participates in this
+regulatory pathway. Suppressors of YejM essentiality were identified in lpxC
+and lapB, and LpxC overproduction was shown to be sufficient to allow survival
+of ΔyejM mutants. Furthermore, the stability of LpxC was shown to be
+reduced in cells lacking YejM, and genetic and physical interactions between
+LapB and YejM were detected. Taken together, our results are consistent with a
+model in which YejM directly modulates LpxC turnover by FtsH-LapB to regulate
+LPS synthesis and maintain membrane homeostasis.\nIMPORTANCE The outer membrane
+is a major determinant of the intrinsic antibiotic resistance of Gram-negative
+bacteria. It is composed of both lipopolysaccharide (LPS) and phospholipid, and
+the synthesis of these lipid species must be balanced for the membrane to
+maintain its barrier function in blocking drug entry. In this study, we
+identified an essential protein of unknown function as a key new factor in modulating
+LPS synthesis in the model bacterium Escherichia coli. Our results provide
+novel insight into how this organism and most likely other Gram-negative
+bacteria maintain membrane homeostasis and their intrinsic resistance to
+antibiotics.","container-title":"mBio","DOI":"10.1128/mBio.00939-20","issue":"3","note":"publisher:
+American Society for
+Microbiology","page":"e00939-20","source":"journals.asm.org
+(Atypon)","title":"An Essential Membrane Protein Modulates
+the Proteolysis of LpxC to Control Lipopolysaccharide Synthesis in Escherichia
+coli","URL":"https://journals.asm.org/doi/10.1128/mBio.00939-20","volume":"11","author":[{"family":"Fivenson","given":"Elayne
+M."},{"family":"Bernhardt","given":"Thomas
+G."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",5,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>3</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Fivenson</span>
+& Bernhardt, 2020). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image6.png" o:spid="_x0000_i1027"
+type="#_x0000_t75" style='width:269pt;height:259pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image015.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=359 height=345
+src="Wiki%20Draft%20(1)_files/image016.gif" v:shapes="image6.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Figure X: <span class=SpellE>Pymol</span>
+structure of <span class=SpellE>PbgA</span>. <o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Crystal
+structure of <span class=SpellE>PbgA</span>, an essential inner transmembrane
+protein in <i style='mso-bidi-font-style:normal'>E. coli'' that is used for
+regulating LPS synthesis and outer membrane homeostasis. The C-terminal
+periplasmic domain is depicted in green. The N-terminal domain is a
+five-transmembrane domain depicted in red, yellow, orange, purple, and cyan. <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.2 <span class=SpellE>PbgA</span>
+protein similarity <o:p></o:p></span>'''<p class=MsoNormal><span class=SpellE><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'>PbgA</span></span><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'> is structurally related to <span class=SpellE>LtaS</span>,
+an enzyme found in many gram-positive bacteria that synthesizes lipoteichoic
+acids. <span class=SpellE>PbgA</span>, like <span class=SpellE>LtaS</span>,
+contains a hydrophobic binding pocket in its periplasmic domain that is required
+for protein activity. However, the crystal structure of the <span class=SpellE>PbgA</span>
+domain indicates that it lacks residues required for <span class=SpellE>LtaS</span>
+catalytic activity, so it is unlikely to have a homologous enzymatic function</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"Igh9S5xC","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":619,"uris":["http://zotero.org/users/local/DWdd4k1w/items/HWCQ9FUI"],"itemData":{"id":619,"type":"article-journal","abstract":"Gram-negative
+bacteria are surrounded by a complex cell envelope that includes two membranes.
+The outer membrane prevents many drugs from entering these cells and is thus a
+major determinant of their intrinsic antibiotic resistance. This barrier
+function is imparted by the asymmetric architecture of the membrane with
+lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner
+leaflet. The LPS and phospholipid synthesis pathways share an intermediate.
+Proper membrane biogenesis therefore requires that the flux through each
+pathway be balanced. In Escherichia coli, a major control point in establishing
+this balance is the committed step of LPS synthesis mediated by LpxC. Levels of
+this enzyme are controlled through its degradation by the inner membrane
+protease FtsH and its presumed adapter protein LapB (YciM). How turnover of
+LpxC is controlled has remained unclear for many years. Here, we demonstrate
+that the essential protein of unknown function YejM (PbgA) participates in this
+regulatory pathway. Suppressors of YejM essentiality were identified in lpxC
+and lapB, and LpxC overproduction was shown to be sufficient to allow survival
+of ΔyejM mutants. Furthermore, the stability of LpxC was shown to be
+reduced in cells lacking YejM, and genetic and physical interactions between
+LapB and YejM were detected. Taken together, our results are consistent with a
+model in which YejM directly modulates LpxC turnover by FtsH-LapB to regulate
+LPS synthesis and maintain membrane homeostasis.\nIMPORTANCE The outer membrane
+is a major determinant of the intrinsic antibiotic resistance of Gram-negative
+bacteria. It is composed of both lipopolysaccharide (LPS) and phospholipid, and
+the synthesis of these lipid species must be balanced for the membrane to
+maintain its barrier function in blocking drug entry. In this study, we
+identified an essential protein of unknown function as a key new factor in
+modulating LPS synthesis in the model bacterium Escherichia coli. Our results
+provide novel insight into how this organism and most likely other
+Gram-negative bacteria maintain membrane homeostasis and their intrinsic
+resistance to
+antibiotics.","container-title":"mBio","DOI":"10.1128/mBio.00939-20","issue":"3","note":"publisher:
+American Society for
+Microbiology","page":"e00939-20","source":"journals.asm.org
+(Atypon)","title":"An Essential Membrane Protein Modulates
+the Proteolysis of LpxC to Control Lipopolysaccharide Synthesis in Escherichia
+coli","URL":"https://journals.asm.org/doi/10.1128/mBio.00939-20","volume":"11","author":[{"family":"Fivenson","given":"Elayne
+M."},{"family":"Bernhardt","given":"Thomas
+G."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",5,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>3</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Fivenson</span>
+& Bernhardt, 2020).<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.3 Initial Proposed Function of <span
+class=SpellE>PbgA</span><o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>In
+<i style='mso-bidi-font-style:normal'>S. Typhimurium'', cells that use a
+two-component regulatory system, <span class=SpellE>PhoPQ</span>, require <span
+class=SpellE>PbgA</span> to coordinate this process. The <span class=SpellE>PhoPQ</span>
+system induces changes to the outer membrane to protect cells from infection by
+sensing changes in the environment. One of the changes that occurs is an
+increase in the content of the PL, cardiolipin (CL). <span class=SpellE>PbgA</span>
+was found to bind to CL in vitro and since the deletion of <span class=SpellE>PbgA</span>
+showed no increase in CL content, it led to the assumption that it acts as a
+transporter that brings CL from the inner membrane to the outer membrane</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"uTPTGZpN","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":628,"uris":["http://zotero.org/users/local/DWdd4k1w/items/K232PHWH"],"itemData":{"id":628,"type":"article-journal","abstract":"Gram-negative
+bacteria produce an asymmetric outer membrane (OM) that is particularly
+impermeant to many antibiotics and characterized by lipopolysaccharide (LPS)
+exclusively at the cell surface. LPS biogenesis remains an ideal target for
+therapeutic intervention, as disruption could kill bacteria or increase
+sensitivity to existing antibiotics. While it has been known that LPS synthesis
+is regulated by proteolytic control of LpxC, the enzyme that catalyzes the
+first committed step of LPS synthesis, it remains unknown which signals direct
+this regulation. New details have been revealed during study of a cryptic
+essential inner membrane protein, YejM. Multiple functions have been proposed
+over the years for YejM, including a controversial hypothesis that it
+transports cardiolipin from the inner membrane to the OM. Strong evidence now
+indicates that YejM senses LPS in the periplasm and directs proteolytic
+regulation. Here, we discuss the standing literature of YejM and highlight
+exciting new insights into cell envelope
+maintenance.","container-title":"mBio","DOI":"10.1128/mBio.02624-20","issue":"6","note":"publisher:
+American Society for Microbiology","page":"e02624-20","source":"journals.asm.org
+(Atypon)","title":"Restoring Balance to the Outer Membrane:
+YejM’s Role in LPS Regulation","title-short":"Restoring
+Balance to the Outer Membrane","URL":"https://journals.asm.org/doi/10.1128/mBio.02624-20","volume":"11","author":[{"family":"Simpson","given":"Brent
+W."},{"family":"Douglass","given":"Martin
+V."},{"family":"Trent","given":"M.
+Stephen"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",12,15]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>12</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Simpson et al., 2020). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>However,
+other studies have shown that <span class=SpellE>PbgA</span> may not act as a
+cardiolipin transporter as it lacks an outer membrane partner while other
+complexes that transport substrates from the inner membrane to the outer
+membrane have inner membrane, periplasmic, and outer membrane components.
+Additionally, if <span class=SpellE>PbgA</span> were essential for cardiolipin
+synthesis, then it would be expected that cardiolipin deficiency would lead to
+toxic levels of <span class=SpellE>PbgA</span>, but this does not occur.
+Finally, because <span class=SpellE>PbgA</span> is known to have an impact on
+outer membrane permeability, but truncations of <span class=SpellE>PbgA</span>
+periplasmic domain show outer membrane permeability defects, indicating that
+both the inner membrane and periplasmic domain of <span class=SpellE>PbgA</span>
+are involved in the same function. Therefore, it is unlikely that <span
+class=SpellE>PbgA</span> is involved in cardiolipin transport</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"FLnydd47","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":628,"uris":["http://zotero.org/users/local/DWdd4k1w/items/K232PHWH"],"itemData":{"id":628,"type":"article-journal","abstract":"Gram-negative
+bacteria produce an asymmetric outer membrane (OM) that is particularly
+impermeant to many antibiotics and characterized by lipopolysaccharide (LPS)
+exclusively at the cell surface. LPS biogenesis remains an ideal target for
+therapeutic intervention, as disruption could kill bacteria or increase
+sensitivity to existing antibiotics. While it has been known that LPS synthesis
+is regulated by proteolytic control of LpxC, the enzyme that catalyzes the
+first committed step of LPS synthesis, it remains unknown which signals direct
+this regulation. New details have been revealed during study of a cryptic
+essential inner membrane protein, YejM. Multiple functions have been proposed
+over the years for YejM, including a controversial hypothesis that it
+transports cardiolipin from the inner membrane to the OM. Strong evidence now
+indicates that YejM senses LPS in the periplasm and directs proteolytic
+regulation. Here, we discuss the standing literature of YejM and highlight
+exciting new insights into cell envelope
+maintenance.","container-title":"mBio","DOI":"10.1128/mBio.02624-20","issue":"6","note":"publisher:
+American Society for
+Microbiology","page":"e02624-20","source":"journals.asm.org
+(Atypon)","title":"Restoring Balance to the Outer Membrane:
+YejM’s Role in LPS Regulation","title-short":"Restoring
+Balance to the Outer Membrane","URL":"https://journals.asm.org/doi/10.1128/mBio.02624-20","volume":"11","author":[{"family":"Simpson","given":"Brent
+W."},{"family":"Douglass","given":"Martin
+V."},{"family":"Trent","given":"M.
+Stephen"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",12,15]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>12</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Simpson et al., 2020). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.4 Novel Discovery of <span
+class=SpellE>PbgA</span> Function<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>A
+recent study suggests that <span class=SpellE>PbgA</span> serves a larger but
+undefined role in envelope assembly, such as preventing excessive turnover of <span
+class=SpellE>LpxC</span> and promoting <span class=SpellE>LpxC</span>
+accumulation by shielding it from the <span class=SpellE>FtsH-LapB</span>
+proteolytic system. They also found that the N-terminal transmembrane of <span
+class=SpellE>PbgA</span> alone interacts with the <span class=SpellE>LapB</span>
+component of the <span class=SpellE>FtsH-LapB</span> proteolytic system to
+promote <span class=SpellE>LpxC</span> accumulation</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"OfDNMfny","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":619,"uris":["http://zotero.org/users/local/DWdd4k1w/items/HWCQ9FUI"],"itemData":{"id":619,"type":"article-journal","abstract":"Gram-negative
+bacteria are surrounded by a complex cell envelope that includes two membranes.
+The outer membrane prevents many drugs from entering these cells and is thus a
+major determinant of their intrinsic antibiotic resistance. This barrier
+function is imparted by the asymmetric architecture of the membrane with
+lipopolysaccharide (LPS) in the outer leaflet and phospholipids in the inner
+leaflet. The LPS and phospholipid synthesis pathways share an intermediate.
+Proper membrane biogenesis therefore requires that the flux through each
+pathway be balanced. In Escherichia coli, a major control point in establishing
+this balance is the committed step of LPS synthesis mediated by LpxC. Levels of
+this enzyme are controlled through its degradation by the inner membrane
+protease FtsH and its presumed adapter protein LapB (YciM). How turnover of
+LpxC is controlled has remained unclear for many years. Here, we demonstrate
+that the essential protein of unknown function YejM (PbgA) participates in this
+regulatory pathway. Suppressors of YejM essentiality were identified in lpxC
+and lapB, and LpxC overproduction was shown to be sufficient to allow survival
+of ΔyejM mutants. Furthermore, the stability of LpxC was shown to be
+reduced in cells lacking YejM, and genetic and physical interactions between
+LapB and YejM were detected. Taken together, our results are consistent with a
+model in which YejM directly modulates LpxC turnover by FtsH-LapB to regulate
+LPS synthesis and maintain membrane homeostasis.\nIMPORTANCE The outer membrane
+is a major determinant of the intrinsic antibiotic resistance of Gram-negative
+bacteria. It is composed of both lipopolysaccharide (LPS) and phospholipid, and
+the synthesis of these lipid species must be balanced for the membrane to
+maintain its barrier function in blocking drug entry. In this study, we
+identified an essential protein of unknown function as a key new factor in
+modulating LPS synthesis in the model bacterium Escherichia coli. Our results
+provide novel insight into how this organism and most likely other
+Gram-negative bacteria maintain membrane homeostasis and their intrinsic
+resistance to
+antibiotics.","container-title":"mBio","DOI":"10.1128/mBio.00939-20","issue":"3","note":"publisher:
+American Society for
+Microbiology","page":"e00939-20","source":"journals.asm.org
+(Atypon)","title":"An Essential Membrane Protein Modulates
+the Proteolysis of LpxC to Control Lipopolysaccharide Synthesis in Escherichia
+coli","URL":"https://journals.asm.org/doi/10.1128/mBio.00939-20","volume":"11","author":[{"family":"Fivenson","given":"Elayne
+M."},{"family":"Bernhardt","given":"Thomas
+G."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",5,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>3</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Fivenson</span>
+& Bernhardt, 2020).<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><span
+style='mso-spacerun:yes'> </span><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Polymyxin Antibiotics and Antibiotic
+Resistance:<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.1. Polymyxin Antibiotics<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Polymyxins
+are an important class of antibiotics used in the treatment of systemic
+infections caused by multidrug-resistant gram-negative bacteria such as
+pseudomonas aeruginosa</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"wRfcvQq5","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin
+as a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). Currently, these antibiotics are
+used as a last line of treatment against such infections</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"n7wlnoFI","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin as
+a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). The main drugs in clinical use
+within this antibiotic class are Polymyxin B and Polymyxin E (also called
+colistin), which target infections of the urinary tract, meninges, and
+bloodstream</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"tYAD01ia","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin
+as a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls Publishing","publisher-place":"Treasure
+Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.2. Mechanism of Action of Colistin<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Polymyxins
+target the lipid A core of LPS</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"7ZVsLxVx","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":612,"uris":["http://zotero.org/users/local/DWdd4k1w/items/S5FNUZAL"],"itemData":{"id":612,"type":"article-journal","abstract":"Lipopolysaccharide
+(LPS) resides in the outer membrane of Gram-negative bacteria where it is
+responsible for barrier function1,2. LPS can cause death as a result of septic
+shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite
+the clinical importance of polymyxins and the emergence of multidrug resistant
+strains5, our understanding of the bacterial factors that regulate LPS
+biogenesis is incomplete. Here we characterize the inner membrane protein PbgA
+and report that its depletion attenuates the virulence of Escherichia coli by
+reducing levels of LPS and outer membrane integrity. In contrast to previous
+claims that PbgA functions as a cardiolipin transporter6–9, our structural
+analyses and physiological studies identify a lipid A-binding motif along the
+periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides
+selectively bind to LPS in vitro and inhibit the growth of diverse
+Gram-negative bacteria, including polymyxin-resistant strains. Proteomic,
+genetic and pharmacological experiments uncover a model in which direct
+periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by
+regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10–12.
+In summary, we find that PbgA has an unexpected but essential role in the
+regulation of LPS biogenesis, presents a new structural basis for the selective
+recognition of lipids, and provides opportunities for future antibiotic
+discovery.","container-title":"Nature","DOI":"10.1038/s41586-020-2597-x","ISSN":"1476-4687","issue":"7821","language":"en","license":"2020
+The Author(s), under exclusive licence to Springer Nature
+Limited","note":"number: 7821\npublisher: Nature Publishing
+Group","page":"479-483","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of the essential inner membrane lipopolysaccharide–PbgA
+complex","URL":"http://www.nature.com/articles/s41586-020-2597-x","volume":"584","author":[{"family":"Clairfeuille","given":"Thomas"},{"family":"Buchholz","given":"Kerry
+R."},{"family":"Li","given":"Qingling"},{"family":"Verschueren","given":"Erik"},{"family":"Liu","given":"Peter"},{"family":"Sangaraju","given":"Dewakar"},{"family":"Park","given":"Summer"},{"family":"Noland","given":"Cameron
+L."},{"family":"Storek","given":"Kelly
+M."},{"family":"Nickerson","given":"Nicholas
+N."},{"family":"Martin","given":"Lynn"},{"family":"Dela
+Vega","given":"Trisha"},{"family":"Miu","given":"Anh"},{"family":"Reeder","given":"Janina"},{"family":"Ruiz-Gonzalez","given":"Maria"},{"family":"Swem","given":"Danielle"},{"family":"Han","given":"Guanghui"},{"family":"DePonte","given":"Daniel
+P."},{"family":"Hunter","given":"Mark
+S."},{"family":"Gati","given":"Cornelius"},{"family":"Shahidi-Latham","given":"Sheerin"},{"family":"Xu","given":"Min"},{"family":"Skelton","given":"Nicholas"},{"family":"Sellers","given":"Benjamin
+D."},{"family":"Skippington","given":"Elizabeth"},{"family":"Sandoval","given":"Wendy"},{"family":"Hanan","given":"Emily
+J."},{"family":"Payandeh","given":"Jian"},{"family":"Rutherford","given":"Steven
+T."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>14</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Clairfeuille</span>
+et al., 2020). These antibiotics destabilize the PLs and LPS present in the
+outer membrane of gram-negative bacteria</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"c9oHqDO2","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This activity
+reviews the indications, action, and contraindications for polymyxin as a
+valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls Publishing","publisher-place":"Treasure
+Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). Since polymyxins are positively
+charged, they electrostatically interact with the phosphate groups on both of
+the negatively charged phosphorylated sugars that make up lipid A</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"Htyh6yVV","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin
+as a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island (FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID: 32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). This causes the divalent cations
+(such as calcium and magnesium) from the phosphate groups within the membrane
+lipids to become displaced, creating increased permeability</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"dd4opF7M","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This activity
+reviews the indications, action, and contraindications for polymyxin as a
+valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls Publishing","publisher-place":"Treasure
+Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). This leads to the outer membrane
+becoming disrupted, allowing small molecules and other intracellular contents
+to leak out of the cell and cause bacterial cell death</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"KQVXUWc2","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin
+as a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains of
+gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island (FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID: 32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). <o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>In
+addition, polymyxins can neutralize the endotoxin effect of pathogens</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"jz6XGLzg","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This activity
+reviews the indications, action, and contraindications for polymyxin as a
+valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). Since the endotoxic part of
+gram-negative bacteria corresponds to the lipid A core, polymyxins can bind to
+the LPS that was released as a result of cellular death</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"Clnnlrv8","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin
+as a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island (FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022). This results in the neutralization
+of the endotoxin, preventing its effects in circulation</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"PhtPbk2K","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/local/DWdd4k1w/items/U2DBWKJG"],"itemData":{"id":608,"type":"chapter","abstract":"Polymyxins
+are a class of medications used in the management and treatment of systemic
+infections caused by susceptible strains of multidrug-resistant organisms such
+as Pseudomonas aeruginosa. It is in the antibiotic class of drugs. This
+activity reviews the indications, action, and contraindications for polymyxin
+as a valuable agent in the treatment of multidrug-resistant infections. This
+activity will highlight the mechanism of action, adverse event profile, and
+other key factors pertinent for members of the interprofessional team in the
+treatment of patients with polymyxins who are infected by susceptible strains
+of gram-negative pathogens resistant most of the other antibiotic
+classes.","call-number":"NBK557540","container-title":"StatPearls","event-place":"Treasure
+Island
+(FL)","language":"eng","license":"Copyright
+© 2022, StatPearls Publishing LLC.","note":"PMID:
+32491472","publisher":"StatPearls
+Publishing","publisher-place":"Treasure Island
+(FL)","source":"PubMed","title":"Polymyxin","URL":"http://www.ncbi.nlm.nih.gov/books/NBK557540/","author":[{"family":"Shatri","given":"Genti"},{"family":"Tadi","given":"Prasanna"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>13</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Shatri</span>
+& <span class=SpellE>Tadi</span>, 2022).<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image3.png" o:spid="_x0000_i1026"
+type="#_x0000_t75" style='width:457pt;height:217.5pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image017.png" o:title=""
+cropbottom="1110f" cropleft="630f" cropright="528f"/></v:shape><![endif]--><![if !vml]><img border=0 width=609 height=290
+src="Wiki%20Draft%20(1)_files/image018.gif" v:shapes="image3.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Figure X:</span>'''<span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> Colistin electrostatically
+interacts with the lipid A core of LPS, creating a disruption of the membrane
+and allowing small molecules to leak out of the cell.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>X.3. Antibiotic Resistance<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Polymyxins
+are an extremely important and clinically relevant class of drugs since they
+are the last line of <span class=SpellE>defence</span> against gram-negative
+bacteria that are resistant to all other antibiotics</span><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"1nRHZKva","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":612,"uris":["http://zotero.org/users/local/DWdd4k1w/items/S5FNUZAL"],"itemData":{"id":612,"type":"article-journal","abstract":"Lipopolysaccharide
+(LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible
+for barrier function1,2. LPS can cause death as a result of septic shock, and
+its lipid A core is the target of polymyxin antibiotics3,4. Despite the
+clinical importance of polymyxins and the emergence of multidrug resistant
+strains5, our understanding of the bacterial factors that regulate LPS
+biogenesis is incomplete. Here we characterize the inner membrane protein PbgA
+and report that its depletion attenuates the virulence of Escherichia coli by
+reducing levels of LPS and outer membrane integrity. In contrast to previous
+claims that PbgA functions as a cardiolipin transporter6–9, our structural
+analyses and physiological studies identify a lipid A-binding motif along the
+periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides
+selectively bind to LPS in vitro and inhibit the growth of diverse
+Gram-negative bacteria, including polymyxin-resistant strains. Proteomic,
+genetic and pharmacological experiments uncover a model in which direct
+periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by
+regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme10–12.
+In summary, we find that PbgA has an unexpected but essential role in the
+regulation of LPS biogenesis, presents a new structural basis for the selective
+recognition of lipids, and provides opportunities for future antibiotic
+discovery.","container-title":"Nature","DOI":"10.1038/s41586-020-2597-x","ISSN":"1476-4687","issue":"7821","language":"en","license":"2020
+The Author(s), under exclusive licence to Springer Nature
+Limited","note":"number: 7821\npublisher: Nature Publishing
+Group","page":"479-483","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of the essential inner membrane lipopolysaccharide–PbgA
+complex","URL":"http://www.nature.com/articles/s41586-020-2597-x","volume":"584","author":[{"family":"Clairfeuille","given":"Thomas"},{"family":"Buchholz","given":"Kerry
+R."},{"family":"Li","given":"Qingling"},{"family":"Verschueren","given":"Erik"},{"family":"Liu","given":"Peter"},{"family":"Sangaraju","given":"Dewakar"},{"family":"Park","given":"Summer"},{"family":"Noland","given":"Cameron
+L."},{"family":"Storek","given":"Kelly
+M."},{"family":"Nickerson","given":"Nicholas
+N."},{"family":"Martin","given":"Lynn"},{"family":"Dela
+Vega","given":"Trisha"},{"family":"Miu","given":"Anh"},{"family":"Reeder","given":"Janina"},{"family":"Ruiz-Gonzalez","given":"Maria"},{"family":"Swem","given":"Danielle"},{"family":"Han","given":"Guanghui"},{"family":"DePonte","given":"Daniel
+P."},{"family":"Hunter","given":"Mark
+S."},{"family":"Gati","given":"Cornelius"},{"family":"Shahidi-Latham","given":"Sheerin"},{"family":"Xu","given":"Min"},{"family":"Skelton","given":"Nicholas"},{"family":"Sellers","given":"Benjamin
+D."},{"family":"Skippington","given":"Elizabeth"},{"family":"Sandoval","given":"Wendy"},{"family":"Hanan","given":"Emily
+J."},{"family":"Payandeh","given":"Jian"},{"family":"Rutherford","given":"Steven
+T."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>14</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Clairfeuille</span>
+et al., 2020). Unfortunately, there is an emergence of bacteria that are also
+resistant to polymyxins</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"d0lBYWG3","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":612,"uris":["http://zotero.org/users/local/DWdd4k1w/items/S5FNUZAL"],"itemData":{"id":612,"type":"article-journal","abstract":"Lipopolysaccharide
+(LPS) resides in the outer membrane of Gram-negative bacteria where it is
+responsible for barrier function1,2. LPS can cause death as a result of septic
+shock, and its lipid A core is the target of polymyxin antibiotics3,4. Despite
+the clinical importance of polymyxins and the emergence of multidrug resistant
+strains5, our understanding of the bacterial factors that regulate LPS
+biogenesis is incomplete. Here we characterize the inner membrane protein PbgA
+and report that its depletion attenuates the virulence of Escherichia coli by
+reducing levels of LPS and outer membrane integrity. In contrast to previous
+claims that PbgA functions as a cardiolipin transporter6–9, our structural
+analyses and physiological studies identify a lipid A-binding motif along the
+periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides
+selectively bind to LPS in vitro and inhibit the growth of diverse
+Gram-negative bacteria, including polymyxin-resistant strains. Proteomic,
+genetic and pharmacological experiments uncover a model in which direct periplasmic
+sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating
+the stability of LpxC, a key cytoplasmic biosynthetic enzyme10–12. In summary,
+we find that PbgA has an unexpected but essential role in the regulation of LPS
+biogenesis, presents a new structural basis for the selective recognition of
+lipids, and provides opportunities for future antibiotic
+discovery.","container-title":"Nature","DOI":"10.1038/s41586-020-2597-x","ISSN":"1476-4687","issue":"7821","language":"en","license":"2020
+The Author(s), under exclusive licence to Springer Nature
+Limited","note":"number: 7821\npublisher: Nature Publishing
+Group","page":"479-483","source":"www-nature-com.libaccess.lib.mcmaster.ca","title":"Structure
+of the essential inner membrane lipopolysaccharide–PbgA
+complex","URL":"http://www.nature.com/articles/s41586-020-2597-x","volume":"584","author":[{"family":"Clairfeuille","given":"Thomas"},{"family":"Buchholz","given":"Kerry
+R."},{"family":"Li","given":"Qingling"},{"family":"Verschueren","given":"Erik"},{"family":"Liu","given":"Peter"},{"family":"Sangaraju","given":"Dewakar"},{"family":"Park","given":"Summer"},{"family":"Noland","given":"Cameron
+L."},{"family":"Storek","given":"Kelly
+M."},{"family":"Nickerson","given":"Nicholas
+N."},{"family":"Martin","given":"Lynn"},{"family":"Dela
+Vega","given":"Trisha"},{"family":"Miu","given":"Anh"},{"family":"Reeder","given":"Janina"},{"family":"Ruiz-Gonzalez","given":"Maria"},{"family":"Swem","given":"Danielle"},{"family":"Han","given":"Guanghui"},{"family":"DePonte","given":"Daniel
+P."},{"family":"Hunter","given":"Mark
+S."},{"family":"Gati","given":"Cornelius"},{"family":"Shahidi-Latham","given":"Sheerin"},{"family":"Xu","given":"Min"},{"family":"Skelton","given":"Nicholas"},{"family":"Sellers","given":"Benjamin
+D."},{"family":"Skippington","given":"Elizabeth"},{"family":"Sandoval","given":"Wendy"},{"family":"Hanan","given":"Emily
+J."},{"family":"Payandeh","given":"Jian"},{"family":"Rutherford","given":"Steven
+T."}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>14</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (<span class=SpellE>Clairfeuille</span>
+et al., 2020). One bacterial resistance mechanism that has been discovered is
+due to the expression of <span class=SpellE>EptA</span>, a protein part of the
+same family as PbgA</span><!--[if supportFields]><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-begin'></span>
+ADDIN ZOTERO_ITEM CSL_CITATION
+{"citationID":"ZB2uPOlP","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":610,"uris":["http://zotero.org/users/local/DWdd4k1w/items/4G5T5MW8"],"itemData":{"id":610,"type":"article-journal","abstract":"Polymyxins,
+a family of cationic antimicrobial cyclic peptides, act as a last line of
+defense against severe infections by Gram-negative pathogens with carbapenem
+resistance. In addition to the intrinsic resistance to polymyxin E (colistin)
+conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance
+gene mcr-1 has been disseminated globally since the first discovery in Southern
+China, in late 2015. However, the molecular mechanisms for both intrinsic and
+transferable resistance to colistin remain largely unknown. Here, we aim to
+address this gap in the knowledge of these proteins. Structural and functional
+analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity
+that is required for the entry of the lipid substrate, phosphatidylethanolamine
+(PE). The in vitro and in vivo data together have allowed us to visualize the
+similarities in catalytic activity shared by EptA and MCR-1 and -2. The
+expression of either EptA or MCR-1 or -2 is shown to remodel the surface of
+enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella
+pneumoniae, etc.), rendering them resistant to colistin. The parallels in the
+PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a
+comprehensive understanding of both intrinsic and transferable colistin
+resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two
+domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase)
+are not functionally exchangeable. Taken together, the results represent a
+common mechanism for intrinsic and transferable PEA resistance to polymyxin, a
+last-resort antibiotic against multidrug-resistant pathogens.\nIMPORTANCE EptA
+and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to
+colistin, a final resort against carbapenem-resistant pathogens. Structural and
+functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid
+substrate-recognizing cavities, which explains intrinsic and transferable
+colistin resistance in gut bacteria. A similar mechanism is proposed for the
+catalytic activities of EptA and MCR-1 and -2. Together, they constitute a
+common mechanism for intrinsic and transferable polymyxin
+resistance.","container-title":"mBio","DOI":"10.1128/mBio.02317-17","issue":"2","note":"publisher:
+American Society for
+Microbiology","page":"e02317-17","source":"journals.asm.org
+(Atypon)","title":"An Evolutionarily Conserved Mechanism
+for Intrinsic and Transferable Polymyxin Resistance","URL":"https://journals.asm.org/doi/full/10.1128/mBio.02317-17","volume":"9","author":[{"family":"Xu","given":"Yongchang"},{"family":"Wei","given":"Wenhui"},{"family":"Lei","given":"Sheng"},{"family":"Lin","given":"Jingxia"},{"family":"Srinivas","given":"Swaminath"},{"family":"Feng","given":"Youjun"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2018",4,10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>15</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Xu et al., 2018). This protein has
+been shown to remodel the surface of the bacteria, making it resistant to
+colistin</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"W7GaEfgH","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":610,"uris":["http://zotero.org/users/local/DWdd4k1w/items/4G5T5MW8"],"itemData":{"id":610,"type":"article-journal","abstract":"Polymyxins,
+a family of cationic antimicrobial cyclic peptides, act as a last line of
+defense against severe infections by Gram-negative pathogens with carbapenem
+resistance. In addition to the intrinsic resistance to polymyxin E (colistin)
+conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance
+gene mcr-1 has been disseminated globally since the first discovery in Southern
+China, in late 2015. However, the molecular mechanisms for both intrinsic and
+transferable resistance to colistin remain largely unknown. Here, we aim to
+address this gap in the knowledge of these proteins. Structural and functional
+analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity
+that is required for the entry of the lipid substrate, phosphatidylethanolamine
+(PE). The in vitro and in vivo data together have allowed us to visualize the
+similarities in catalytic activity shared by EptA and MCR-1 and -2. The
+expression of either EptA or MCR-1 or -2 is shown to remodel the surface of
+enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella
+pneumoniae, etc.), rendering them resistant to colistin. The parallels in the
+PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a
+comprehensive understanding of both intrinsic and transferable colistin
+resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two
+domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase)
+are not functionally exchangeable. Taken together, the results represent a
+common mechanism for intrinsic and transferable PEA resistance to polymyxin, a
+last-resort antibiotic against multidrug-resistant pathogens.\nIMPORTANCE EptA
+and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to
+colistin, a final resort against carbapenem-resistant pathogens. Structural and
+functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid
+substrate-recognizing cavities, which explains intrinsic and transferable colistin
+resistance in gut bacteria. A similar mechanism is proposed for the catalytic
+activities of EptA and MCR-1 and -2. Together, they constitute a common
+mechanism for intrinsic and transferable polymyxin
+resistance.","container-title":"mBio","DOI":"10.1128/mBio.02317-17","issue":"2","note":"publisher:
+American Society for
+Microbiology","page":"e02317-17","source":"journals.asm.org
+(Atypon)","title":"An Evolutionarily Conserved Mechanism
+for Intrinsic and Transferable Polymyxin
+Resistance","URL":"https://journals.asm.org/doi/full/10.1128/mBio.02317-17","volume":"9","author":[{"family":"Xu","given":"Yongchang"},{"family":"Wei","given":"Wenhui"},{"family":"Lei","given":"Sheng"},{"family":"Lin","given":"Jingxia"},{"family":"Srinivas","given":"Swaminath"},{"family":"Feng","given":"Youjun"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2018",4,10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>15</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Xu et al., 2018). <span
+class=SpellE>EptA</span> does this by modifying the phosphate groups on both of
+the phosphorylated sugars on lipid A; thereby, reducing its overall negative
+charge</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"wH3osBJS","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":610,"uris":["http://zotero.org/users/local/DWdd4k1w/items/4G5T5MW8"],"itemData":{"id":610,"type":"article-journal","abstract":"Polymyxins,
+a family of cationic antimicrobial cyclic peptides, act as a last line of
+defense against severe infections by Gram-negative pathogens with carbapenem
+resistance. In addition to the intrinsic resistance to polymyxin E (colistin)
+conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance
+gene mcr-1 has been disseminated globally since the first discovery in Southern
+China, in late 2015. However, the molecular mechanisms for both intrinsic and
+transferable resistance to colistin remain largely unknown. Here, we aim to
+address this gap in the knowledge of these proteins. Structural and functional
+analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that
+is required for the entry of the lipid substrate, phosphatidylethanolamine
+(PE). The in vitro and in vivo data together have allowed us to visualize the
+similarities in catalytic activity shared by EptA and MCR-1 and -2. The
+expression of either EptA or MCR-1 or -2 is shown to remodel the surface of
+enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella
+pneumoniae, etc.), rendering them resistant to colistin. The parallels in the
+PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a
+comprehensive understanding of both intrinsic and transferable colistin
+resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two
+domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase)
+are not functionally exchangeable. Taken together, the results represent a
+common mechanism for intrinsic and transferable PEA resistance to polymyxin, a
+last-resort antibiotic against multidrug-resistant pathogens.\nIMPORTANCE EptA
+and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to
+colistin, a final resort against carbapenem-resistant pathogens. Structural and
+functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid
+substrate-recognizing cavities, which explains intrinsic and transferable
+colistin resistance in gut bacteria. A similar mechanism is proposed for the
+catalytic activities of EptA and MCR-1 and -2. Together, they constitute a
+common mechanism for intrinsic and transferable polymyxin
+resistance.","container-title":"mBio","DOI":"10.1128/mBio.02317-17","issue":"2","note":"publisher:
+American Society for
+Microbiology","page":"e02317-17","source":"journals.asm.org
+(Atypon)","title":"An Evolutionarily Conserved Mechanism
+for Intrinsic and Transferable Polymyxin Resistance","URL":"https://journals.asm.org/doi/full/10.1128/mBio.02317-17","volume":"9","author":[{"family":"Xu","given":"Yongchang"},{"family":"Wei","given":"Wenhui"},{"family":"Lei","given":"Sheng"},{"family":"Lin","given":"Jingxia"},{"family":"Srinivas","given":"Swaminath"},{"family":"Feng","given":"Youjun"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2018",4,10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>15</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Xu et al., 2018). This makes the
+bacteria resistant to polymyxins because they can no longer have the previously
+mentioned electrostatic interactions and thus cannot bind to the modified lipid
+A core</span><!--[if supportFields]><span lang=EN style='font-size:12.0pt;
+line-height:115%;font-family:"Times New Roman",serif;mso-fareast-font-family:
+"Times New Roman"'><span style='mso-element:field-begin'></span> ADDIN
+ZOTERO_ITEM CSL_CITATION
+{"citationID":"Ev7M9sq2","properties":{"formattedCitation":"\\super
+\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":610,"uris":["http://zotero.org/users/local/DWdd4k1w/items/4G5T5MW8"],"itemData":{"id":610,"type":"article-journal","abstract":"Polymyxins,
+a family of cationic antimicrobial cyclic peptides, act as a last line of
+defense against severe infections by Gram-negative pathogens with carbapenem
+resistance. In addition to the intrinsic resistance to polymyxin E (colistin)
+conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance
+gene mcr-1 has been disseminated globally since the first discovery in Southern
+China, in late 2015. However, the molecular mechanisms for both intrinsic and
+transferable resistance to colistin remain largely unknown. Here, we aim to
+address this gap in the knowledge of these proteins. Structural and functional
+analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity
+that is required for the entry of the lipid substrate, phosphatidylethanolamine
+(PE). The in vitro and in vivo data together have allowed us to visualize the
+similarities in catalytic activity shared by EptA and MCR-1 and -2. The
+expression of either EptA or MCR-1 or -2 is shown to remodel the surface of
+enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella
+pneumoniae, etc.), rendering them resistant to colistin. The parallels in the
+PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a
+comprehensive understanding of both intrinsic and transferable colistin
+resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two
+domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase)
+are not functionally exchangeable. Taken together, the results represent a
+common mechanism for intrinsic and transferable PEA resistance to polymyxin, a
+last-resort antibiotic against multidrug-resistant pathogens.\nIMPORTANCE EptA
+and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to
+colistin, a final resort against carbapenem-resistant pathogens. Structural and
+functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid
+substrate-recognizing cavities, which explains intrinsic and transferable
+colistin resistance in gut bacteria. A similar mechanism is proposed for the
+catalytic activities of EptA and MCR-1 and -2. Together, they constitute a
+common mechanism for intrinsic and transferable polymyxin
+resistance.","container-title":"mBio","DOI":"10.1128/mBio.02317-17","issue":"2","note":"publisher:
+American Society for
+Microbiology","page":"e02317-17","source":"journals.asm.org
+(Atypon)","title":"An Evolutionarily Conserved Mechanism
+for Intrinsic and Transferable Polymyxin Resistance","URL":"https://journals.asm.org/doi/full/10.1128/mBio.02317-17","volume":"9","author":[{"family":"Xu","given":"Yongchang"},{"family":"Wei","given":"Wenhui"},{"family":"Lei","given":"Sheng"},{"family":"Lin","given":"Jingxia"},{"family":"Srinivas","given":"Swaminath"},{"family":"Feng","given":"Youjun"}],"accessed":{"date-parts":[["2023",2,1]]},"issued":{"date-parts":[["2018",4,10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"}
+<span style='mso-element:field-separator'></span></span><![endif]--><sup><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif'>15</span></sup><!--[if supportFields]><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><span style='mso-element:field-end'></span></span><![endif]--><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'> (Xu et al., 2018). With polymyxin
+resistance becoming a bigger problem, more research on <span class=SpellE>PbgA</span>
+will be beneficial for future antibiotic discovery.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";
+mso-no-proof:yes'><!--[if gte vml 1]><v:shape id="image2.png" o:spid="_x0000_i1025"
+type="#_x0000_t75" style='width:468pt;height:134pt;visibility:visible;
+mso-wrap-style:square'><v:imagedata src="Wiki%20Draft%20(1)_files/image019.png" o:title=""/></v:shape><![endif]--><![if !vml]><img border=0 width=624 height=179
+src="Wiki%20Draft%20(1)_files/image020.gif" v:shapes="image2.png"><![endif]></span><span
+lang=EN style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Figure X: </span>'''<span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>The enzyme <span class=SpellE>EptA</span>
+modifies LPS and reduces the negative charge of lipid A; therefore, prevents
+colistin from binding and makes bacteria resistant to the antibiotic.<o:p></o:p></span><p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span>'''<p class=MsoNormal><b style='mso-bidi-font-weight:normal'><span lang=EN
+style='font-size:12.0pt;line-height:115%;font-family:"Times New Roman",serif;
+mso-fareast-font-family:"Times New Roman"'>Conclusion:<o:p></o:p></span>'''<p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'>Antibiotic
+resistance is a growing concern today and for our future. Gram-negative
+bacteria have been particularly associated with antibiotic resistance due to the
+presence of LPS in their cell wall, <span class=GramE>acting<span
+style='mso-spacerun:yes'>  </span>as</span> a protective barrier against drugs.
+The ability of these bacteria to rapidly evolve and develop resistance to
+antibiotics has made it an ongoing challenge for scientists to find new ways to
+combat these infections. Understanding the pathways in which LPS is synthesized
+and regulated demonstrates importance pertaining to antibiotic drug targeting. <span
+class=SpellE>Clairfeullie</span> et al. contribute to this research through
+characterizing <span class=SpellE>PbgA</span> and demonstrating how
+manipulation of this protein could possibly be utilized in the lowering of LPS
+levels and subsequently virulence by <i style='mso-bidi-font-style:normal'>E.
+coli''.<o:p></o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span><p class=MsoNormal><span lang=EN style='font-size:12.0pt;line-height:115%;
+font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman"'><o:p> </o:p></span></div></body></html>

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