A strategy for antagonizing quorum sensing

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / metabolism
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Binding Sites
  • Biofilms / drug effects*
  • Chromobacterium / drug effects*
  • Chromobacterium / genetics
  • Chromobacterium / growth & development
  • Chromobacterium / metabolism
  • Chromobacterium / pathogenicity
  • Crystallography, X-Ray
  • DNA / metabolism
  • Dose-Response Relationship, Drug
  • Lactones / chemistry
  • Lactones / metabolism
  • Lactones / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Protein Conformation
  • Quorum Sensing / drug effects*
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Structure-Activity Relationship
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Virulence

Substances

  • Anti-Bacterial Agents
  • Lactones
  • Ligands
  • N-hexanoyl-L-homoserine lactone
  • Repressor Proteins
  • Trans-Activators
  • LuxR autoinducer binding proteins
  • DNA
  • 4-Butyrolactone

Associated data

  • PDB/3QP1
  • PDB/3QP2
  • PDB/3QP4
  • PDB/3QP5
  • PDB/3QP6
  • PDB/3QP8