title: Structure-Based Design and Biological Evaluation of Triphenyl Scaffold-Based Hybrid Compounds as Hydrolytically Stable Modulators of a LuxR-Type Quorum Sensing Receptor.
abstract: Many common bacterial pathogens utilize quorum sensing to coordinate group behaviors and initiate virulence at high cell densities. The use of small molecules to block quorum sensing provides a means of abrogating pathogenic phenotypes, but many known quorum sensing modulators have limitations, including hydrolytic instability and displaying non-monotonic dose curves (indicative of additional targets and/or modes of action). To address these issues, we undertook a structure-based scaffold-hopping approach to develop new chemical modulators of the LasR quorum sensing receptor inPseudomonas aeruginosa. We combined components from a triphenyl derivative known to strongly agonize LasR with chemical moieties known for LasR antagonism and generated potent LasR antagonists that are hydrolytically stable across a range of pH values. Additionally, many of these antagonists do not exhibit non-monotonic dose effects, delivering probes that inhibit LasR across a wider range of assay conditions relative to known lactone-based ligands.
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison , 1101 University Avenue, Madison, Wisconsin 53706, United States.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: O'Reilly
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison , 1101 University Avenue, Madison, Wisconsin 53706, United States.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Blackwell
keywords: LasR receptor; Pseudomonas aeruginosa; anti-infectives; quorum sensing; small molecule probes; virulence