title: Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa: an in vivo potent antivirulence agent targeting pqs quorum sensing.
abstract: The virulence regulator PqsR of Pseudomonas aeruginosa is considered as an attractive target for attenuating the bacterial pathogenicity without eliciting resistance. However, despite efforts and desires, no promising PqsR antagonist has been discovered thus far. Now, a surprising functionality change of a highly affine PqsR antagonist in P. aeruginosa is revealed, which is mediated by a bacterial signal molecule synthase and responsible for low cellular potency. Blockade of the susceptible position led to the discovery of the first antivirulence compound that is potent in vivo and targets PqsR, thus providing a proof of concept for this novel antivirulence therapy.
authors: Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany).
authors: Cenbin
authors: C
authors: Lu
authors: Christine K
authors: CK
authors: Maurer
authors: Benjamin
authors: B
authors: Kirsch
authors: Anke
authors: A
authors: Steinbach
authors: Rolf W
authors: RW
authors: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins
keywords: antivirulence; drug discovery; inhibitors; medicinal chemistry; resistance