Document Detail


Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli.
MedLine Citation:
PMID:  23665139     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The presence of lipopolysaccharide (LPS) in the outer leaflet of the outer membrane (OM) of Gram-negative bacteria creates a permeability barrier that prevents the entry of most currently available antibiotics. The seven lipopolysaccharide transport (Lpt) proteins involved in transporting and assembling this glycolipid are essential for growth and division in Escherichia coli; therefore, inhibiting their functions leads to cell death. LptB, the ATPase that provides energy for LPS transport and assembly, forms a complex with three other inner membrane (IM) components, LptC, F, and G. We demonstrate that inhibitors of pure LptB can also inhibit the full IM complex, LptBFGC, purified in detergent. We also compare inhibition of LptB and the LptBFGC complex with the antibiotic activity of these compounds. Our long-term goal is to develop tools to study inhibitors of LPS biogenesis that could serve as potentiators by disrupting the OM permeability barrier, facilitating entry of clinically used antibiotics not normally used to treat Gram-negative infections, or that can serve as antibiotics themselves.
Authors:
David J Sherman; Suguru Okuda; William A Denny; Daniel Kahne
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-04-18
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  21     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-23     Completed Date:  2014-02-19     Revised Date:  2014-08-18    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  4846-51     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / antagonists & inhibitors*,  genetics,  metabolism
Anti-Bacterial Agents / chemistry,  pharmacology
Biological Transport
Cell Wall / metabolism
Escherichia coli / drug effects,  metabolism*
Escherichia coli Proteins / antagonists & inhibitors*,  genetics,  metabolism
Lipopolysaccharides / metabolism*
Microbial Sensitivity Tests
Recombinant Fusion Proteins / biosynthesis,  chemistry,  genetics
Small Molecule Libraries / chemistry,  pharmacology
Grant Support
ID/Acronym/Agency:
GM066174/GM/NIGMS NIH HHS; R01 AI081059/AI/NIAID NIH HHS; R01 GM066174/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Escherichia coli Proteins; 0/Lipopolysaccharides; 0/Recombinant Fusion Proteins; 0/Small Molecule Libraries
Comments/Corrections

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