Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios

Quorum sensing (QS) is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress viru...

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Bibliographic Details
Published in:PLoS pathogens 2012-06, Vol.8 (6), p.e1002767-e1002767
Main Authors: Ng, Wai-Leung, Perez, Lark, Cong, Jianping, Semmelhack, Martin F, Bassler, Bonnie L
Format: Article
Language:English
Subjects:
Bacterial Proteins - metabolism
Bacteriology
Biofilms - growth & development
Biology
Blotting, Western
Chemistry
Cholera
Health aspects
HeLa Cells
High-Throughput Screening Assays
Humans
Microbiology
Mutation
Physiological aspects
Proteins
Quorum sensing
Quorum Sensing - physiology
Structure-Activity Relationship
Vibrio
Vibrio cholerae - pathogenicity
Vibrio cholerae - physiology
Virulence (Microbiology)
Virulence - physiology
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Summary:Quorum sensing (QS) is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1002767