A Strategy for Antagonizing Quorum Sensing

Abstract

SUMMARY Quorum-sensing bacteria communicate via small molecules called autoinducers to coordinate collective behaviors. Because quorum sensing controls virulence factor expression in many clinically relevant pathogens, membrane-permeable quorum sensing antagonists that prevent population-wide expression of virulence genes offer a potential route to novel antibacterial therapeutics. Here, we report a strategy for inhibiting quorum-sensing receptors of the widespread LuxR family. Structure-function studies with natural and synthetic ligands demonstrate that the dimeric LuxR-type transcription factor CviR from Chromobacterium violaceum is potently antagonized by molecules that bind in place of the native acylated homoserine lactone autoinducer, provided that they stabilize a closed conformation. In such conformations, each of the two DNA-binding domains interacts with the ligand-binding domain of the opposing monomer. Consequently, the DNA-binding helices are held apart by ~60 Å, twice the ~30 Å separation required for operator binding. This approach may represent a general strategy for the inhibition of multi-domain proteins.

Acyl-homoserine lactone-dependent eavesdropping promotes competition in a laboratory co-culture model

“…The potential role of each of these receptors in competition has not been determined. AHL receptor specificity can be easily altered by single amino-acid changes (Collins et al, 2005;Hawkins et al, 2007;Chen et al, 2011;Lintz et al, 2011), suggesting that AHL recognition may be very adaptable in nature. In contrast to these broad-specificity AHL receptors, the receptor of the squid symbiont Vibrio fischeri is quite specific for its cognate AHL (Visick and Ruby, 1999).…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…This closed conformation involves the repositioning of the key residue Met89. Importantly, the relative inhibition potencies of the various antagonists were found to directly correlate with the progressive repositioning of the Met89 side chain, a result that helps to explain how small changes in ligand structure can induce large changes in receptor activity (202). For other AHL receptors, including TraR and LasR, the native ligands are postulated to trigger a protein folding switch that is required for proper folding of the receptor, which enhances protein stability (175)(176)(177)(178)(179).…”

“…More recently, structure-function studies and cocrystallization were used to further elucidate the mechanism by which these analogues inhibit CviR activity. The crystal structure of CviR in complex with CL suggests that CL binds in the native ligand-binding pocket and induces the CviR dimer to assume a crossed-domain closed conformation that prevents binding of DNA (202). This closed conformation involves the repositioning of the key residue Met89.…”

QsIA disrupts LasR dimerization in antiactivation of bacterial quorum sensing

“…5). Current structures of LuxR-type regulators show that their dimerization is mainly mediated by their LBDs, whereas their DBDs have a minor role for their dimerization (15,(26)(27)(28). The LBD dimerization of LuxR-type regulators may help to position the DBD dimer in a correct conformation to recognize the target DNA sequence.…”