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The mechanism of pyrimethamine resistance inPlasmodium falciparum

Angela Dieckmann, Alexander Louis-Ferdinand Jung

Abstract

The uptake of radioactive pyrimethamine by a sensitive and a resistant strain of Plasmodium falciparum, the metabolic fate of pyrimethamine inside these parasites and the kinetic properties of dihydrofolate reductase (DHFR) from both strains have been studied. Uptake of the drug was identical in both strains and no metabolite of pyrimethamine was found in either strain. DHFR from the resistant strain was 300 times less sensitive to inhibition by pyrimethamine than the enzyme from the sensitive strain, while the Michaelis constant for dihydrofolate remained unchanged and inhibition was competitive in both cases. Altered properties of plasmodial DHFR are apparently the only mechanism responsible for pyrimethamine resistance in the strain of Plasmodium falciparum studied.

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Key concepts: Dihydrofolate reductase, Pyrimethamine, Plasmodium falciparum, Biology, Strain (injury), Metabolite, Drug resistance, Plasmodium (life cycle)