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

TitleBroad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios.
Publication TypeJournal Article
Year of Publication2012
AuthorsNg, W-L, Perez, L, Cong, J, Semmelhack, MF, Bassler, BL
JournalPLoS Pathog
Volume8
Issue6
Paginatione1002767
Date Published2012
ISSN1553-7374
KeywordsBacterial Proteins, Biofilms, Blotting, Western, HeLa Cells, High-Throughput Screening Assays, Humans, Quorum Sensing, Structure-Activity Relationship, Vibrio cholerae, Virulence
Abstract

<p>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.</p>

DOI10.1371/journal.ppat.1002767
Alternate JournalPLoS Pathog.
PubMed ID22761573
PubMed Central IDPMC3386246
Grant List5R01AI054442 / AI / NIAID NIH HHS / United States
5R01GM065859 / GM / NIGMS NIH HHS / United States
GM082061 / GM / NIGMS NIH HHS / United States
K22 AI099087 / AI / NIAID NIH HHS / United States
MCB-0343821 / / PHS HHS / United States
R01 GM065859 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States