Modulate Bacterial Quorum Sensing with Synth Ligands: Systematic Evaluation of N-Acylated Homoserine Lactone in Multiple Species & New Insights Mechanism of Action

Abstract

Quorum sensing signaling process plays a pivotal role both in the pathogenesis of infectious disease and in beneficial symbioses. There is intense interest in the development of synthetic ligands that can intercept quorum-sensing signals and attenuate these divergent outcomes. Both broad-spectrum and species-selective modulators of quorum sensing hold significant value as small-molecule tools for fundamental studies of this complex cell-cell signaling process and for future biomedical and environmental applications. Here, we report the design and synthesis of focused collections of non-native N-acylated homoserine lactones AHL & systematic eval these ~90 ligands w 3 Gram-negative bacteria [pathogens Agrobacterium tumefaciens & Pseudomonas aeruginosa; model symbiont Vibrio fischeri]. This study is the first to report and compare the activities of a set of ligands across multiple species and has revealed some of the most potent synthetic modulators of quorum sensing. Moreover, several of these ligands exhibit agonistic or antagonistic activity in all three species, while other ligands are only active in one or two species. Analysis of the screening data revealed that at least a subset of these ligands modulate quorum sensing via a partial agonism mechanism. Selected ligands can either inhibit or promote the production of elastase B, a key virulence factor in wild-type P. aeruginosa, depending on their concentrations. Overall, broad insights into the molecular features required for small-molecule inhibition or activation of quorum sensing in Gram-negative bacteria. In addition, expansive set of chemical tools for the further investigation of QS pathways and responses.