Basis for antifolate action and resistance in malaria

Resistance to antifolates of the malaria parasite Plasmodium falciparum stems from stepwise mutations of the target enzyme dihydrofolate reductase (DHFR). New drugs can be developed against resistant parasites, which are assumed to have limited possibilities in mutations. Mechanisms of resistance other than reduced binding of inhibitors to mutant enzymes may be possible and need to be further explored. New synergistic combinations of drugs targeting DHFR and dihydropteroate synthase may be employed, with new provisions against development of resistance.