title: Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa.
abstract: The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K(d,app) of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Cenbin
authors.initials: C
authors.lastname: Lu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kirsch
authors.forename: Christina
authors.initials: C
authors.lastname: Zimmer
authors.forename: Johannes C
authors.initials: JC
authors.lastname: de Jong
authors.forename: Claudia
authors.initials: C
authors.lastname: Henn
authors.forename: Christine K
authors.initials: CK
authors.lastname: Maurer
authors.forename: Mathias
authors.initials: M
authors.lastname: Müsken
authors.forename: Susanne
authors.initials: S
authors.lastname: Häussler
authors.forename: Anke
authors.initials: A
authors.lastname: Steinbach
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D017930:Genes, Reporter; D007700:Kinetics; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism*; D011710:Pyocyanine / Q000096:biosynthesis; D053038:Quorum Sensing / Q000187:drug effects*
chemical_list: D042462:4-Quinolones; D001426:Bacterial Proteins; D011710:Pyocyanine