Abstract
The current epidemic of infections caused by antibiotic-resistant gram-positive bacteria requires the discovery of new drug targets and the development of new therapeutics. Lipoteichoic acid (LTA), a cell wall polymer of gram-positive bacteria, consists of 1,3-polyglycerol-phosphate linked to glycolipid. LTA synthase (LtaS) polymerizes polyglycerol-phosphate from phosphatidylglycerol, a reaction that is essential for the growth of gram-positive bacteria. We screened small molecule libraries for compounds inhibiting growth of Staphylococcus aureus but not of gram-negative bacteria. Compound 1771 [2-oxo-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)ethyl 2-naphtho[2,1-b]furan-1-ylacetate] blocked phosphatidylglycerol binding to LtaS and inhibited LTA synthesis in S. aureus and in Escherichia coli expressing ltaS. Compound 1771 inhibited the growth of antibiotic-resistant gram-positive bacteria and prolonged the survival of mice with lethal S. aureus challenge, validating LtaS as a target for the development of antibiotics.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acyltransferases / antagonists & inhibitors
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Acyltransferases / metabolism
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Animals
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Catalytic Domain
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Disease Models, Animal
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Drug Resistance, Microbial / drug effects
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Lipopolysaccharides / biosynthesis*
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Mice
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Microbial Sensitivity Tests
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Mutation / genetics
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Phosphatidylglycerols / metabolism
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Sepsis / drug therapy
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Sepsis / microbiology
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Sepsis / pathology
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Small Molecule Libraries / therapeutic use
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Staphylococcal Infections / drug therapy
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Staphylococcal Infections / microbiology
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Staphylococcal Infections / pathology
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / enzymology
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Staphylococcus aureus / growth & development
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Staphylococcus aureus / ultrastructure
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Structure-Activity Relationship
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Survival Analysis
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Teichoic Acids / biosynthesis*
Substances
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Lipopolysaccharides
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Phosphatidylglycerols
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Small Molecule Libraries
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Teichoic Acids
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lipoteichoic acid
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Acyltransferases