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Screening for Quorum-Sensing Inhibitors (QSI) by Use of a Novel Genetic System, the QSI Selector

Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, Kgs. Lyngby,¹ Carlsberg Research Center, Biosector, Valby,² Department of Chemistry, Royal Veterinary and Agricultural University of Denmark, Frederiksberg, Denmark,⁴ Lehrstuhl für Mikrobiologie, Technische Universitat München, Freising, Germany,³ Department of Microbiology, University of Zürich, Zürich, Switzerland⁵

Received 10 April 2004/ Accepted 22 October 2004

With the widespread appearance of antibiotic-resistant bacteria, there is an increasing demand for novel strategies to control infectious diseases. Furthermore, it has become apparent that the bacterial life style also contributes significantly to this problem. Bacteria living in the biofilm mode of growth tolerate conventional antimicrobial treatments. The discovery that many bacteria use quorum-sensing (QS) systems to coordinate virulence and biofilm development has pointed out a new, promising target for antimicrobial drugs. We constructed a collection of screening systems, QS inhibitor (QSI) selectors, which enabled us to identify a number of novel QSIs among natural and synthetic compound libraries. The two most active were garlic extract and 4-nitro-pyridine-N-oxide (4-NPO). GeneChip-based transcriptome analysis revealed that garlic extract and 4-NPO had specificity for QS-controlled virulence genes in Pseudomonas aeruginosa. These two QSIs also significantly reduced P. aeruginosa biofilm tolerance to tobramycin treatment as well as virulence in a Caenorhabditis elegans pathogenesis model.

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