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Antimicrobial Agents and Chemotherapy, June 2009, p. 2432-2443, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01283-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Computer-Aided Identification of Recognized Drugs as Pseudomonas aeruginosa Quorum-Sensing Inhibitors{triangledown} ,{dagger}

Liang Yang,1,{ddagger} Morten Theil Rybtke,2,{ddagger} Tim Holm Jakobsen,2 Morten Hentzer,2 Thomas Bjarnsholt,2 Michael Givskov,2 and Tim Tolker-Nielsen2*

Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark,1 Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark2

Received 24 September 2008/ Returned for modification 23 November 2008/ Accepted 28 March 2009

Attenuation of Pseudomonas aeruginosa virulence by the use of small-molecule quorum-sensing inhibitors (referred to as the antipathogenic drug principle) is likely to play a role in future treatment strategies for chronic infections. In this study, structure-based virtual screening was used in a search for putative quorum-sensing inhibitors from a database comprising approved drugs and natural compounds. The database was built from compounds which showed structural similarities to previously reported quorum-sensing inhibitors, the ligand of the P. aeruginosa quorum-sensing receptor LasR, and a quorum-sensing receptor agonist. Six top-ranking compounds, all recognized drugs, were identified and tested for quorum-sensing-inhibitory activity. Three compounds, salicylic acid, nifuroxazide, and chlorzoxazone, showed significant inhibition of quorum-sensing-regulated gene expression and related phenotypes in a dose-dependent manner. These results suggest that the identified compounds have the potential to be used as antipathogenic drugs. Furthermore, the results indicate that structure-based virtual screening is an efficient tool in the search for novel compounds to combat bacterial infections.

* Corresponding author. Mailing address: Department of International Health, Immunology and Microbiology. Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. Phone: 45 353 26656. Fax: 45 353 27853. E-mail: ttn{at}sund.ku.dk

{triangledown} Published ahead of print on 13 April 2009.

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

{ddagger} These authors contributed equally to this work.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2432-2443, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01283-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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