A Strategy for Antagonizing Quorum Sensing

SummaryQuorum-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 multidomain proteins.

Graphical AbstractFigure optionsDownload high-quality image (211 K)Download as PowerPoint slideHighlights
► Quorum-sensing (QS) antagonists represent potential antibacterial therapeutics
► They can bind LuxR-family transcription factors in competition with autoinducers
► The antagonists stabilize a closed conformation incapable of binding operator DNA
► This inhibition strategy may be generalizable to other multidomain receptors