Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 44, Pages 17981-17986Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1316981110
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Funding
- National Institutes of Health (NIH) [P50 GM071508]
- Howard Hughes Medical Institute, NIH [5R01GM065859]
- National Science Foundation [MCB-0343821]
- NIH National Institute of Allergy and Infectious Diseases [F32AI095002]
- Human Frontier Science Program
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [0948112] Funding Source: National Science Foundation
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Quorum sensing is a chemical communication process that bacteria use to regulate collective behaviors. Disabling quorum-sensing circuits with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The human pathogen Pseudomonas aeruginosa uses quorum sensing to control virulence and biofilm formation. Here, we analyze synthetic molecules for inhibition of the two P. aeruginosa quorum-sensing receptors, LasR and RhlR. Our most effective compound, meta-bromo-thiolactone (mBTL), inhibits both the production of the virulence factor pyocyanin and biofilm formation. mBTL also protects Caenorhabditis elegans and human lung epithelial cells from killing by P. aeruginosa. Both LasR and RhlR are partially inhibited bymBTL in vivo and in vitro; however, RhlR, not LasR, is the relevant in vivo target. More potent antagonists do not exhibit superior function in impeding virulence. Because LasR and RhlR reciprocally control crucial virulence factors, appropriately tuning rather than completely inhibiting their activities appears to hold the key to blocking pathogenesis in vivo.
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