Abstract
The lack of suitable antimalarial agents to replace chloroquine and pyrimethamine/sulfadoxine threatens efforts to control the spread of drug-resistant strains of the malaria parasite Plasmodium falciparum. Here we describe a transformation system, involving WR99210 selection of parasites transformed with either wild-type or methotrexate-resistant human dihydrofolate reductase (DHFR), that has application for the screening of P. falciparum-specific DHFR inhibitors that are active against drug-resistant parasites. Using this system, we have found that the prophylactic drug cycloguanil has a mode of pharmacological action distinct from the activity of its parent compound proguanil. Complementation assays demonstrate that cycloguanil acts specifically on P. falciparum DHFR and has no other significant target. The target of proguanil itself is separate from DHFR. We propose a strategy of combination chemotherapy incorporating the use of multiple parasite-specific inhibitors that act at the same molecular target and thereby maintain, in combination, their effectiveness against alternative forms of resistance that arise from different sets of point mutations in the target. This approach could be combined with traditional forms of combination chemotherapy in which two or more compounds are used against separate targets.
Footnotes
- Received July 10, 1998.
- Accepted September 14, 1998.
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Send reprint requests to: Dr. Thomas E. Wellems, Malaria Genetics Section, LPD, NIAID, Building 4, Room 126, 4 Center Drive, MSC 0425, NIH, Bethesda, MD 20892-0425. E-mail:tew{at}helix.nih.gov
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↵1 Permanent address: Unité de Parasitologie Bio-Médicale, Institut Pasteur, 75724 Paris Cedex 15, France.
- The American Society for Pharmacology and Experimental Therapeutics
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