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Resistance of vivax malaria to treatment with antifolates, such as pyrimethamine (Pyr), is spreading as mutations in the dihydrofolatereductase (dhfr) genes are selected and disseminated. We tested the antitumor drug methotrexate (MTX), a potent competitive inhibitor of dhfr, against 11 Plasmodium vivax isolates ex vivo, 10 of which had multiple dhfr mutations associated with Pyr resistance. Despite high-grade resistance to Pyr (median 50% inhibitory concentration [IC₅₀], 13,345 nM), these parasites were all highly susceptible to MTX (median IC₅₀, 2.6 nM). Given its potency against Pyr-resistant P. vivax, the antimalarial potential of MTX deserves further investigation.

Original publication

DOI

10.1093/infdis/jiq024

Type

Journal article

Journal

J Infect Dis

Publication Date

15/01/2011

Volume

203

Pages

207 - 210

Keywords

Antimalarials, Drug Resistance, Humans, Inhibitory Concentration 50, Malaria, Vivax, Methotrexate, Mutation, Missense, Plasmodium vivax, Protozoan Proteins, Pyrimethamine, Tetrahydrofolate Dehydrogenase