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Antimicrobial Agents and Chemotherapy, November 2006, p. 3674-3679, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00665-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Pseudomonas aeruginosa Quorum-Sensing Inhibitors Identified in an Ultra-High-Throughput Screen ^,

Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139,¹ Department of Microbiology, University of Washington, 1959 NE Pacific St., HSB I-420, Seattle, Washington 98195,² Vertex Pharmaceuticals Incorporated, 11010 Torreyana Rd., San Diego, California 92121³

Received 31 May 2006/ Returned for modification 9 August 2006/ Accepted 1 September 2006

The opportunistic pathogen Pseudomonas aeruginosa has two complete acyl-homoserine lactone (acyl-HSL) signaling systems, LasR-LasI and RhlR-RhlI. LasI catalyzes the synthesis of N-3-oxododecanoyl homoserine lactone (3OC12-HSL), and LasR is a transcription factor that requires 3OC12-HSL as a ligand. RhlI catalyzes the synthesis of N-butanoyl homoserine lactone (C₄), and RhlR is a transcription factor that responds to C₄. LasR and RhlR control the transcription of hundreds of P. aeruginosa genes, many of which are critical virulence determinants, and LasR is required for RhlR function. We developed an ultra-high-throughput cell-based assay to screen a library of approximately 200,000 compounds for inhibitors of LasR-dependent gene expression. Although the library contained a large variety of chemical structures, the two best inhibitors resembled the acyl-homoserine lactone molecule that normally binds to LasR. One compound, a tetrazole with a 12-carbon alkyl tail designated PD12, had a 50% inhibitory concentration (IC₅₀) of 30 nM. The second compound, V-06-018, had an IC₅₀ of 10 µM and is a phenyl ring with a 12-carbon alkyl tail. A microarray analysis showed that both compounds were general inhibitors of quorum sensing, i.e., the expression levels of most LasR-dependent genes were affected. Both compounds also inhibited the production of two quorum-sensing-dependent virulence factors, elastase and pyocyanin. These compounds should be useful for studies of LasR-dependent gene regulation and might serve as scaffolds for the identification of new quorum-sensing modulators.

Published ahead of print on 11 September 2006.

Supplemental material for this article may be found at http://aac.asm.org/.

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