Title | A strategy for antagonizing quorum sensing. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Chen, G, Swem, LR, Swem, DL, Stauff, DL, O'Loughlin, CT, Jeffrey, PD, Bassler, BL, Hughson, FM |
Journal | Mol Cell |
Volume | 42 |
Issue | 2 |
Pagination | 199-209 |
Date Published | 2011 Apr 22 |
ISSN | 1097-4164 |
Keywords | 4-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> |
DOI | 10.1016/j.molcel.2011.04.003 |
Alternate Journal | Mol Cell |
PubMed ID | 21504831 |
PubMed Central ID | PMC3092643 |
Grant List | R01 GM065859 / GM / NIGMS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States R01 AI054442 / AI / NIAID NIH HHS / United States P30 EB009998 / EB / NIBIB NIH HHS / United States GM065859 / GM / NIGMS NIH HHS / United States AI054442 / AI / NIAID NIH HHS / United States R37 GM065859 / GM / NIGMS NIH HHS / United States R01 AI054442-10 / AI / NIAID NIH HHS / United States |