Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase.
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.
Fidock
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Malaria Genetics Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0425, USA.
Nomura
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Wellems
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D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology; D005816:Genetic Complementation Test; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008727:Methotrexate / Q000494:pharmacology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D002727:Proguanil / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D014227:Triazines / Q000494:pharmacology*
D000962:Antimalarials; D005493:Folic Acid Antagonists; D014227:Triazines; C026009:cycloguanil; D019271:Hypoxanthine; C006201:BRL 6231; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D008727:Methotrexate