title: Identification of small-molecule antagonists of the Pseudomonas aeruginosa transcriptional regulator PqsR: biophysically guided hit discovery and optimization.
abstract: The Gram-negative pathogen Pseudomonas aeruginosa produces an intercellular alkyl quinolone signaling molecule, the Pseudomonas quinolone signal. The pqs quorum sensing communication system that is characteristic for P. aeruginosa regulates the production of virulence factors. Therefore, we consider the pqs system a novel target to limit P. aeruginosa pathogenicity. Here, we present small molecules targeting a key player of the pqs system, PqsR. A rational design strategy in combination with surface plasmon resonance biosensor analysis led to the identification of PqsR binders. Determination of thermodynamic binding signatures and functional characterization in E. coli guided the hit optimization, resulting in the potent hydroxamic acid derived PqsR antagonist 11 (IC(50) = 12.5 μM). Remarkably it displayed a comparable potency in P. aeruginosa (IC(50) = 23.6 μM) and reduced the production of the virulence factor pyocyanin. Beyond this, site-directed mutagenesis together with thermodynamic analysis provided insights into the energetic characteristics of protein-ligand interactions. Thus the identified PqsR antagonists are promising scaffolds for further drug design efforts against this important pathogen.
authors: Helmholtz-Institute for Pharmaceutical Research Saarland  (HIPS), Campus C2.3, 66123 Saarbrücken, Germany.
authors: Tobias
authors: T
authors: Klein
authors: Claudia
authors: C
authors: Henn
authors: Johannes C
authors: JC
authors: de Jong
authors: Christina
authors: C
authors: Zimmer
authors: Benjamin
authors: B
authors: Kirsch
authors: Christine K
authors: CK
authors: Maurer
authors: Dominik
authors: D
authors: Pistorius
authors: Rolf
authors: R
authors: Müller
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 / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000235:genetics* / Q000378:metabolism; D015363:Quinolones / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015363:Quinolones; D054852:Small Molecule Libraries