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Antimicrobial Agents and Chemotherapy, August 2006, p. 2658-2665, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.01412-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cisplatin Inhibition of Anthrax Lethal Toxin

Mahtab Moayeri, Jason F. Wiggins, Robin E. Lindeman, and Stephen H. Leppla*

Bacterial Toxins and Therapeutics Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 1 November 2005/ Returned for modification 26 January 2006/ Accepted 9 May 2006

Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages derived from certain inbred strains. LT is comprised of a receptor binding component, protective antigen (PA), which delivers the enzymatic component, lethal factor (LF), into cells. We found that mouse macrophages were protected from toxin by the antitumor drug cis-diammineplatinum (II) dichloride (cisplatin). Cisplatin was shown to inhibit LT-mediated cleavage of cellular mitogen-activated protein kinases (MEKs) without inhibiting LF's in vitro proteolytic activity. Cisplatin-treated PA lost 100% of its ability to function in toxicity assays when paired with untreated LF, despite maintaining the ability to bind to cells. Cisplatin-treated PA was unable to form heptameric oligomers required for LF binding and translocation. The drug was shown to modify PA in a reversible noncovalent manner. Not surprisingly, cisplatin also blocked the actions of anthrax edema toxin and of LF-Pseudomonas aeruginosa exotoxin A fusion peptide (FP59), both of which require PA for translocation. Treatment of BALB/cJ mice or Fischer F344 rats with cisplatin at biologically relevant concentrations completely protected the animals from a coadministered lethal dose of LT. However, treatment with cisplatin 2 hours before or after animals received a lethal bolus of toxin did not protect them.

* Corresponding author. Mailing address: National Institutes of Health, Building 30, Room 303, Bethesda, MD 20892. Phone: (301) 594-2865. Fax: (301) 480-0326. E-mail: sleppla{at}niaid.nih.gov.

Antimicrobial Agents and Chemotherapy, August 2006, p. 2658-2665, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.01412-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sanchez, A. M., Thomas, D., Gillespie, E. J., Damoiseaux, R., Rogers, J., Saxe, J. P., Huang, J., Manchester, M., Bradley, K. A. (2007). Amiodarone and Bepridil Inhibit Anthrax Toxin Entry into Host Cells. Antimicrob. Agents Chemother. 51: 2403-2411 [Abstract] [Full Text]  


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