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Antimicrobial Agents and Chemotherapy, August 2005, p. 3234-3238, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3234-3238.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Lipophilic Antifolate Trimetrexate Is a Potent Inhibitor of Trypanosoma cruzi: Prospect for Chemotherapy of Chagas' Disease

Olga Senkovich,1,2,{dagger} Vandanajay Bhatia,3,{dagger} Nisha Garg,3 and Debasish Chattopadhyay1,2*

Division of Geographic Medicine,1 Center for Biophysical Sciences & Engineering, University of Alabama at Birmingham, Birmingham, Alabama 35294,2 Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas 775553

Received 10 January 2005/ Returned for modification 28 March 2005/ Accepted 20 April 2005

Trypanosoma cruzi, a protozoan parasite, is the causative agent for Chagas' disease, which poses serious public health problem in Latin America. The two drugs available for the treatment of this disease are effective only against recent infections and are toxic. Dihydrofolate reductase (DHFR) has a proven track record as a drug target. The lipophilic antifolate trimetrexate (TMQ), which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients, is a potent inhibitor of T. cruzi DHFR activity, with an inhibitory constant of 6.6 nM. The compound is also highly effective in killing T. cruzi parasites. The 50 and 90% lethal dose values against the trypomastigote are 19 and 36 nM, and the corresponding values for the amastigote form are 26 and 72 nM, respectively. However, as TMQ is also a good inhibitor of human DHFR, further improvement of the selectivity of this drug would be preferable. Identification of a novel antifolate selective against T. cruzi would open up new therapeutic avenues for treatment of Chagas' disease.

* Corresponding author. Mailing address: University of Alabama at Birmingham, CBSE-250, 1025 18th Street South, Birmingham, AL 35294. Phone: (205) 934-0124. Fax: (205) 975-0538. E-mail: debasish{at}cbse.uab.edu.

{dagger} O.S. and V.B. contributed equally to the work.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3234-3238, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3234-3238.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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