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Antimicrobial Agents and Chemotherapy, October 2005, p. 4101-4109, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4101-4109.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Transcriptional Inhibitor of Virulence Factors in Enteropathogenic Escherichia coli

Annick Gauthier ,1,{dagger},{ddagger} Marilyn L. Robertson,1,{dagger} Michael Lowden,1 J. Antonio Ibarra,2 José Luis Puente,2 and B. Brett Finlay1*

Michael Smith Laboratories and Departments of Biochemistry and Microbiology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,1 Departamento de Biología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62210, Mexico2

Received 24 January 2005/ Returned for modification 29 April 2005/ Accepted 18 July 2005

The type III secretion system (TTSS) is a key virulence mechanism of many important gram-negative bacterial pathogens. The TTSS is conserved among different bacterial pathogens, and mutations and deletions to the system significantly decrease virulence, making the TTSS an important potential therapeutic target. We have developed a high-throughput assay to search for inhibitors of the TTSS. We screened a commercial library of 20,000 small molecules for their ability to inhibit type III secretion by enteropathogenic Escherichia coli (EPEC). After discarding compounds that had no effect on secretion, inhibited bacterial growth, and/or caused degradation of EPEC-secreted proteins, the search was focused on a class of compounds that, while not direct inhibitors of type III secretion, inhibit expression of TTSS-related genes and other genes involved in virulence. This class of compounds does not affect bacterial viability or motility, indicating that it is not significantly affecting the expression of essential genes and is specific to virulence-associated genes. Transcriptional fusion assays confirmed that virulence-associated promoters were more sensitive to inhibition by this class of compounds. Overall, we have identified a class of compounds that can be used as a tool to probe the mechanism(s) that regulates virulence gene expression in EPEC.

* Corresponding author. Mailing address: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada. Phone: 604 822 2210. Fax: 604 822 9830. E-mail: bfinlay{at}interchange.ubc.ca.

{dagger} A.G. and M.L.R. contributed equally to this work.

{ddagger} Present address: Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Avenue, New York, NY 10021.

Antimicrobial Agents and Chemotherapy, October 2005, p. 4101-4109, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4101-4109.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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