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Antimicrobial Agents and Chemotherapy, July 2007, p. 2403-2411, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01184-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Amiodarone and Bepridil Inhibit Anthrax Toxin Entry into Host Cells{triangledown}

Ana M. Sanchez,1 Diane Thomas,4 Eugene J. Gillespie,1 Robert Damoiseaux,2 Joseph Rogers,2 Jonathan P. Saxe,3 Jing Huang,2,3 Marianne Manchester,4 and Kenneth A. Bradley1,2*

Department of Microbiology, Immunology & Molecular Genetics,1 Molecular Screening Shared Resource,2 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California 90095,3 Center for Integrative Molecular Biosciences, The Scripps Research Institute, La Jolla, California 920374

Received 21 September 2006/ Returned for modification 22 October 2006/ Accepted 24 April 2007

Anthrax lethal toxin is one of the fundamental components believed to be responsible for the virulence of Bacillus anthracis. In order to find novel compounds with anti-lethal toxin properties, we used a cell-based assay to screen a collection of approximately 500 small molecules. Nineteen compounds that blocked lethal toxin-mediated killing of RAW 264.7 macrophages were identified, and we report here on the characterization of the two most potent antitoxic compounds, amiodarone and bepridil. These drugs are used to treat cardiac arrhythmia or angina in humans at doses similar to those that provide protection against lethal toxin in vitro. Our results support a model whereby the antitoxic properties of both drugs result from their ability to block endosomal acidification, thereby blocking toxin entry. Amiodarone was tested in vivo and found to significantly increase survival of lethal toxin-challenged Fischer rats.

* Corresponding author. Mailing address: Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, 609 Charles E. Young Drive East, Los Angeles, CA 90095. Phone: (310) 206-7465. Fax: (310) 206-5231. E-mail: kbradley{at}microbio.ucla.edu

{triangledown} Published ahead of print on 7 May 2007.

Antimicrobial Agents and Chemotherapy, July 2007, p. 2403-2411, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01184-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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