title: Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors.
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.
authors.affiliation: School of Life Sciences, Centre for Biomolecular Sciences, University of Nottingham , Nottingham, NG7 2RD, U.K.
authors.forename: Ewan J
authors.initials: EJ
authors.lastname: Murray
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Crowley
authors.forename: Alex
authors.initials: A
authors.lastname: Truman
authors.forename: Simon R
authors.initials: SR
authors.lastname: Clarke
authors.forename: James A
authors.initials: JA
authors.lastname: Cottam
authors.forename: Gopal P
authors.initials: GP
authors.lastname: Jadhav
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Steele
authors.forename: Paul
authors.initials: P
authors.lastname: O'Shea
authors.forename: Catharina
authors.initials: C
authors.lastname: Lindholm
authors.forename: Alan
authors.initials: A
authors.lastname: Cockayne
authors.forename: Siri Ram
authors.initials: SR
authors.lastname: Chhabra
authors.forename: Weng C
authors.initials: WC
authors.lastname: Chan
authors.forename: Paul
authors.initials: P
authors.lastname: Williams
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects; D002460:Cell Line; D005663:Furans / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D009296:Nasal Cavity / Q000166:cytology; D010456:Peptides, Cyclic / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000187:drug effects; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology; D053038:Quorum Sensing / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C414532:AgrD protein, Staphylococcus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005663:Furans; D007202:Indicators and Reagents; D007502:Iron Chelating Agents; D010456:Peptides, Cyclic; D011760:Pyrrolidinones; D054852:Small Molecule Libraries; C009435:tetramic acid; D011494:Protein Kinases; C531166:AgrC protein, Staphylococcus; C003422:tetronic acid