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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{triangledown} ,{dagger}

Ute Müh,1* Martin Schuster,2 Roger Heim,3 Ashvani Singh,3 Eric R. Olson,1 and E. Peter Greenberg2

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.

* Corresponding author. Mailing address: Vertex Pharmaceuticals Inc., 2501 Crosspark Rd., MTF E160, Coralville, IA 52241. Phone: (319) 335-4760. Fax: (319) 335-4508. E-mail: ute_muh{at}vrtx.com.

{triangledown} Published ahead of print on 11 September 2006.

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

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.



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