Broad Spectrum Pro-Quorum-Sensing Molecules as Inhibitors of Virulence in Vibrios

PLoS Pathogens

Bonnie L. Bassler¹  Jianping Cong¹  Wai-Leung Ng²  Martin F. Semmelhack²  Lark Perez³ 

[1] Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America;Department of Molecular Biology, Princeton University, Princeton, New Jersey, United States of America;Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America

关键词: Vibrio cholerae;    Adenosine triphosphatase;    Virulence factors;    Regulator genes;    Vibrio;    ATP hydrolysis;    Cytotoxicity;    HeLa cells;   

DOI  :  10.1371/journal.ppat.1002767

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY