Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors

Ewan J. Murray, Rebecca C. Crowley, Alex Truman, Simon R. Clarke, James A. Cottam, Gopal P. Jadhav, Victoria R. Steele, Paul O'Shea, Catharina Lindholm, Alan Cockayne, Siri Ram Chhabra, Weng C. Chan, Paul Williams

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49 Scopus citations

Abstract

A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

Original languageEnglish (US)
Pages (from-to)2813-2819
Number of pages7
JournalJournal of Medicinal Chemistry
Volume57
Issue number6
DOIs
StatePublished - Mar 27 2014

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Murray, E. J., Crowley, R. C., Truman, A., Clarke, S. R., Cottam, J. A., Jadhav, G. P., Steele, V. R., O'Shea, P., Lindholm, C., Cockayne, A., Chhabra, S. R., Chan, W. C., & Williams, P. (2014). Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors. Journal of Medicinal Chemistry, 57(6), 2813-2819. https://doi.org/10.1021/jm500215s