title: A strategy for antagonizing quorum sensing.
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.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Guozhou
authors.initials: G
authors.lastname: Chen
authors.forename: Lee R
authors.initials: LR
authors.lastname: Swem
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Swem
authors.forename: Devin L
authors.initials: DL
authors.lastname: Stauff
authors.forename: Colleen T
authors.initials: CT
authors.lastname: O'Loughlin
authors.forename: Philip D
authors.initials: PD
authors.lastname: Jeffrey
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Bassler
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hughson
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018441:Biofilms / Q000187:drug effects*; D002861:Chromobacterium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011487:Protein Conformation; D053038:Quorum Sensing / Q000187:drug effects*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D007783:Lactones; D008024:Ligands; C104908:N-hexanoyl-L-homoserine lactone; D012097:Repressor Proteins; D015534:Trans-Activators; C064778:LuxR autoinducer binding proteins; D004247:DNA; D015107:4-Butyrolactone