A strategy for antagonizing quorum sensing.

TitleA strategy for antagonizing quorum sensing.
Publication TypeJournal Article
Year of Publication2011
AuthorsChen, G, Swem, LR, Swem, DL, Stauff, DL, O'Loughlin, CT, Jeffrey, PD, Bassler, BL, Hughson, FM
JournalMol Cell
Volume42
Issue2
Pagination199-209
Date Published2011 Apr 22
ISSN1097-4164
Keywords4-Butyrolactone, Anti-Bacterial Agents, Binding Sites, Biofilms, Chromobacterium, Crystallography, X-Ray, DNA, Dose-Response Relationship, Drug, Lactones, Ligands, Models, Molecular, Molecular Structure, Mutation, Protein Conformation, Quorum Sensing, Repressor Proteins, Structure-Activity Relationship, Trans-Activators, Virulence
Abstract

<p>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.</p>

DOI10.1016/j.molcel.2011.04.003
Alternate JournalMol. Cell
PubMed ID21504831
PubMed Central IDPMC3092643
Grant ListAI054442 / AI / NIAID NIH HHS / United States
GM065859 / GM / NIGMS NIH HHS / United States
P30 EB009998 / EB / NIBIB NIH HHS / United States
R01 AI054442 / AI / NIAID NIH HHS / United States
R01 AI054442-10 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States