A Strategy for Antagonizing Quorum Sensing

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2011.04.003· OSTI ID:1042039

Chen, G; Swem, L; Swem, D; Stauff, D; OLoughlin, C; Jeffrey, P; Bassler, B; Hughson, F

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 {approx}60 {angstrom}, twice the {approx}30 {angstrom} separation required for operator binding. This approach may represent a general strategy for the inhibition of multidomain proteins.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1042039
• Report Number(s): BNL--97717-2012-JA
• Journal Information: Molecular Cell, Journal Name: Molecular Cell Journal Issue: 2 Vol. 42; ISSN 1097-2765
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
BACTERIA
GENES
LACTONES
PATHOGENS
PROTEINS
TRANSCRIPTION FACTORS
VIRULENCE