Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria
Open Access
- 11 February 2013
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 110 (9), 3531-3536
- https://doi.org/10.1073/pnas.1217337110
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.Keywords
This publication has 44 references indexed in Scilit:
- Synthesis of Lipoteichoic Acids in Bacillus anthracisJournal of Bacteriology, 2012
- MRSA epidemic linked to a quickly spreading colonization and virulence determinantNature Medicine, 2012
- Population biology of Gram-positive pathogens: high-risk clones for dissemination of antibiotic resistanceFEMS Microbiology Reviews, 2011
- Location, synthesis and function of glycolipids and polyglycerolphosphate lipoteichoic acid in Gram-positive bacteria of the phylum FirmicutesFEMS Microbiology Letters, 2011
- Enzymatic activities and functional interdependencies of Bacillus subtilis lipoteichoic acid synthesis enzymesMolecular Microbiology, 2010
- Community-associated meticillin-resistant Staphylococcus aureusThe Lancet, 2010
- Two‐enzyme systems for glycolipid and polyglycerolphosphate lipoteichoic acid synthesis in Listeria monocytogenesMolecular Microbiology, 2009
- Distinct and essential morphogenic functions for wall- and lipo-teichoic acids in Bacillus subtilisThe EMBO Journal, 2009
- Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaSProceedings of the National Academy of Sciences of the United States of America, 2009
- Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureusProceedings of the National Academy of Sciences of the United States of America, 2007