title: Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria.
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.
authors: Argonne National Laboratory, Argonne, IL 60439, USA.
authors: Stefan G
authors: SG
authors: Richter
authors: Derek
authors: D
authors: Elli
authors: Hwan Keun
authors: HK
authors: Kim
authors: Antoni P A
authors: AP
authors: Hendrickx
authors: Joseph A
authors: JA
authors: Sorg
authors: Olaf
authors: O
authors: Schneewind
authors: Dominique
authors: D
authors: Missiakas
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain; D004195:Disease Models, Animal; D004352:Drug Resistance, Microbial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D010715:Phosphatidylglycerols / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D016019:Survival Analysis; D013682:Teichoic Acids / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010715:Phosphatidylglycerols; D054852:Small Molecule Libraries; D013682:Teichoic Acids; C009900:lipoteichoic acid; D000217:Acyltransferases
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