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Antimicrobial Agents and Chemotherapy, October 2007, p. 3582-3590, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00506-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

High-Throughput Screens for Small-Molecule Inhibitors of Pseudomonas aeruginosa Biofilm Development ^,

Lauren M. Junker and Jon Clardy^*

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115

Received 13 April 2007/ Returned for modification 15 May 2007/ Accepted 23 July 2007

Pseudomonas aeruginosa is both a model biofilm-forming organism and an opportunistic pathogen responsible for chronic lung infections in cystic fibrosis (CF) patients and infections in burn patients, among other maladies. Here we describe the development of an efficient high-throughput screen to identify small-molecule modulators of biofilm formation. This screen has been run with 66,095 compounds to identify those that prevent biofilm formation without affecting planktonic bacterial growth. The screen is a luminescence-based attachment assay that has been validated with several strains of P. aeruginosa and compared to a well-established but low-throughput crystal violet staining biofilm assay. P. aeruginosa strain PAO1 was selected for use in the screen both because it forms robust biofilms and because genetic information and tools are available for the organism. The attachment-inhibited mutant, strain PAO1 fliC, was used as a screening-positive control. We have also developed and validated a complementary biofilm detachment assay that can be used as an alternative primary screen or secondary screen for the attachment screening-positive compounds. We have determined the potencies of 61 compounds against biofilm attachment and have identified 30 compounds that fall into different structural classes as biofilm attachment inhibitors with 50% effective concentrations of less than 20 µM. These small-molecule inhibitors could lead to the identification of their relevant biofilm targets or potential therapeutics for P. aeruginosa infections.

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* Corresponding author. Mailing address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, C-643, Boston, MA 02115. Phone: (617) 432-2845. Fax: (617) 432-6424. E-mail: jon_clardy{at}hms.harvard.edu

Published ahead of print on 30 July 2007.

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

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Antimicrobial Agents and Chemotherapy, October 2007, p. 3582-3590, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00506-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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