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Antimicrobial Agents and Chemotherapy, December 2007, p. 4324-4328, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00680-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation Treat Toxoplasma gondii and Encephalitozoon cuniculi Infection

Department of Medicine (Hematology and Medical Oncology), Tulane University School of Medicine, 1430 Tulane Avenue SL-78, New Orleans, Louisiana 70112,¹ Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Room TC2101, Ann Arbor, Michigan 48109-0346,² San Antonio Cancer Institute, University of Texas Health Sciences Center, 2040 Babcock Rd., Suite 201, San Antonio, Texas 78229,³ Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112,⁴ Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine, Washington, DC 20037,⁵ The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey⁶

Received 23 May 2007/ Returned for modification 5 August 2007/ Accepted 25 September 2007

We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.

Published ahead of print on 8 October 2007.