title: Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.
abstract: Increasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility. In this work, the antagonists were structurally modified to become more soluble, and their structure-activity as well as structure-property relationships were studied. A novel promising compound with improved solubility and enhanced anti-virulence activity was discovered (IC50: 3.8 μM, pyocyanin). Our findings emphasize the crucial role of substituents at the 3-position and the carbonyl group at the 4-position for ligand-receptor interactions, and illuminate the way for further optimization of PqsR antagonists as anti-virulence agents.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Cenbin
authors.initials: C
authors.lastname: Lu
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kirsch
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Maurer
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: de Jong
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Braunshausen
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Steinbach
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Campus C2.3, 66123 Saarbrücken, Germany; Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D015363:Quinolones / Q000037:antagonists & inhibitors*; D053038:Quorum Sensing / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship; D014774:Virulence / Q000187:drug effects; D014867:Water / Q000737:chemistry
chemical_list: C407944:2-heptyl-3-hydroxy-4-quinolone; D000900:Anti-Bacterial Agents; D015363:Quinolones; D014867:Water
keywords: Bacterial communication; PqsR antagonist; Pseudomonas aeruginosa infection; Quorum sensing inhibitor; Structure–activity relationship; Structure–property relationship