A Comparative Analysis of Synthetic Quorum SensingModulators in Pseudomonas aeruginosa: New Insightsinto Mechanism Active Efflux Susceptibility Phenotypic Responseand Next-Generation Ligand Design

摘要

Quorum sensing (QS) is a chemical signaling mechanism that allows bacterial populations to coordinate gene expression in response to social and environmental cues. Many bacterial pathogens use QS to initiate infection at high cell densities. Over the past two decades, chemical antagonists of QS in pathogenic bacteria have attracted substantial interest for use both as tools to further elucidate QS mechanisms and, with further development, potential anti-infective agents. Considerable recent research has been devoted to the design of small molecules capable of modulating the LasR QS receptor in the opportunistic pathogen Pseudomonas aeruginosa. These molecules hold significant promise in a range of contexts; however, as most compounds have been developed independently, comparative activity data for these compounds are scarce. Moreover, the mechanisms by which the bulk of these compounds act are largely unknown. This paucity of data has stalled the choice of an optimal chemical scaffold for further advancement. Herein, we submit the best-characterized LasR modulators to standardized cell-based reporter and QS phenotypic assays in P. aeruginosa, and we report the first comprehensive set of comparative LasR activitydata for these compounds. Our experiments uncovered multiple interestingmechanistic phenomena (including a potential alternative QS-modulatoryligand binding site/partner) that provide new, and unexpected, insightsinto the modes by which many of these LasR ligands act. The lead compounds,data trends, and mechanistic insights reported here will significantlyaid the design of new small molecule QS inhibitors and activatorsin P. aeruginosa, and in other bacteria, withenhanced potencies and defined modes of action.