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Research Article

A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation

Colleen T. O’Loughlin, Laura C. Miller, Albert Siryaporn, Knut Drescher, Martin F. Semmelhack, and Bonnie L. Bassler
  1. Departments of aMolecular Biology,
  2. bChemistry, and
  3. cMechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544; and
  4. dHoward Hughes Medical Institute, Chevy Chase, MD 20815

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PNAS first published October 18, 2013; https://doi.org/10.1073/pnas.1316981110
Colleen T. O’Loughlin
Departments of aMolecular Biology,
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Laura C. Miller
bChemistry, and
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Albert Siryaporn
Departments of aMolecular Biology,
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Knut Drescher
Departments of aMolecular Biology,
cMechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544; and
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Martin F. Semmelhack
bChemistry, and
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Bonnie L. Bassler
Departments of aMolecular Biology,
dHoward Hughes Medical Institute, Chevy Chase, MD 20815
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  • For correspondence: bbassler@princeton.edu
  1. Contributed by Bonnie L. Bassler, September 18, 2013 (sent for review July 23, 2013)

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Significance

In this study, we prepare synthetic molecules and analyze them for inhibition of the Pseudomonas quorum-sensing receptors LasR and RhlR. Our most effective compound, meta-bromo-thiolactone, not only prevents virulence factor expression and biofilm formation but also protects Caenorhabditis elegans and human A549 lung epithelial cells from quorum-sensing–mediated killing by Pseudomonas aeruginosa. This anti–quorum-sensing molecule is capable of influencing P. aeruginosa virulence in tissue culture and animal models. Our findings demonstrate the potential for small-molecule modulators of quorum sensing as therapeutics.

Abstract

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 by mBTL 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.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: bbassler{at}princeton.edu.
  • Author contributions: C.T.O., L.C.M., A.S., K.D., M.F.S., and B.L.B. designed research; C.T.O., L.C.M., A.S., and K.D. performed research; C.T.O., L.C.M., A.S., and K.D. contributed new reagents/analytic tools; C.T.O., L.C.M., A.S., K.D., M.F.S., and B.L.B. analyzed data; and C.T.O., L.C.M., A.S., K.D., M.F.S., and B.L.B. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: The microarray intensity data have been deposited in the Princeton University MicroArray database, http://puma.princeton.edu (PUMA db, http://puma.princeton.edu/cgi-bin/publication/viewPublication.pl?pub_no=558).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1316981110/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Small molecule inhibition of quorum sensing
Colleen T. O’Loughlin, Laura C. Miller, Albert Siryaporn, Knut Drescher, Martin F. Semmelhack, Bonnie L. Bassler
Proceedings of the National Academy of Sciences Oct 2013, 201316981; DOI: 10.1073/pnas.1316981110

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Small molecule inhibition of quorum sensing
Colleen T. O’Loughlin, Laura C. Miller, Albert Siryaporn, Knut Drescher, Martin F. Semmelhack, Bonnie L. Bassler
Proceedings of the National Academy of Sciences Oct 2013, 201316981; DOI: 10.1073/pnas.1316981110
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