Targeting Staphylococcus aureus Quorum Sensing with Nonpeptidic Small Molecule Inhibitors

• Published in: Journal of medicinal chemistry 2014-03, Vol.57 (6), p.2813-2819
• Main Authors: Murray, Ewan J, Crowley, Rebecca C, Truman, Alex, Clarke, Simon R, Cottam, James A, Jadhav, Gopal P, Steele, Victoria R, O’Shea, Paul, Lindholm, Catharina, Cockayne, Alan, Chhabra, Siri Ram, Chan, Weng C, Williams, Paul
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - drug effects; Brief; Cell Line; Furans - chemical synthesis; Furans - pharmacology; Indicators and Reagents; Iron Chelating Agents - pharmacology; Mice; Microbial Sensitivity Tests; Microbiology in the medical area; Mikrobiologi inom det medicinska området; Nasal Cavity - cytology; Peptides, Cyclic - antagonists & inhibitors; Protein Kinases - drug effects; Pyrrolidinones - chemical synthesis; Pyrrolidinones - pharmacology; Quorum Sensing - drug effects; Signal Transduction - drug effects; Small Molecule Libraries; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm500215s

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.