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Mol Cell. 2011 Apr 22;42(2):199-209. doi: 10.1016/j.molcel.2011.04.003.

A strategy for antagonizing quorum sensing.

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1
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

Abstract

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 multidomain proteins.

PMID:
21504831
PMCID:
PMC3092643
DOI:
10.1016/j.molcel.2011.04.003
[Indexed for MEDLINE]
Free PMC Article

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