Title | Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Ng, W-L, Perez, L, Cong, J, Semmelhack, MF, Bassler, BL |
Journal | PLoS Pathog |
Volume | 8 |
Issue | 6 |
Pagination | e1002767 |
Date Published | 2012 |
ISSN | 1553-7374 |
Keywords | Bacterial 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> |
DOI | 10.1371/journal.ppat.1002767 |
Alternate Journal | PLoS Pathog |
PubMed ID | 22761573 |
PubMed Central ID | PMC3386246 |
Grant List | R01 GM065859 / GM / NIGMS NIH HHS / United States 5R01AI054442 / AI / NIAID NIH HHS / United States R01 AI054442 / AI / NIAID NIH HHS / United States K22 AI099087 / AI / NIAID NIH HHS / United States F32 GM082061 / GM / NIGMS NIH HHS / United States MCB-0343821 / / PHS HHS / United States 5R01GM065859 / GM / NIGMS NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States GM082061 / GM / NIGMS NIH HHS / United States |