A Strategy for Antagonizing Quorum Sensing

Guozhou Chen, Lee R. Swem, Danielle L. Swem, Devin L. Stauff, Colleen T. O'Loughlin, Philip D. Jeffrey, Bonnie L. Bassler, Frederick M. Hughson

Research output: Contribution to journalArticle

150 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)199-209
Number of pages11
JournalMolecular Cell
Volume42
Issue number2
DOIs
StatePublished - Apr 22 2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Chen, G., Swem, L. R., Swem, D. L., Stauff, D. L., O'Loughlin, C. T., Jeffrey, P. D., Bassler, B. L., & Hughson, F. M. (2011). A Strategy for Antagonizing Quorum Sensing. Molecular Cell, 42(2), 199-209. https://doi.org/10.1016/j.molcel.2011.04.003