title: Methotrexate is highly potent against pyrimethamine-resistant Plasmodium vivax.
abstract: 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.
authors.affiliation: Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok.
authors.forename: Mallika
authors.initials: M
authors.lastname: Imwong
authors.forename: Bruce
authors.initials: B
authors.lastname: Russell
authors.forename: Rossarin
authors.initials: R
authors.lastname: Suwanarusk
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
authors.forename: Mara L
authors.initials: ML
authors.lastname: Leimanis
authors.forename: Kanlaya
authors.initials: K
authors.lastname: Sriprawat
authors.forename: Supaporn
authors.initials: S
authors.lastname: Kaewpongsri
authors.forename: Aung Pyae
authors.initials: AP
authors.lastname: Phyo
authors.forename: Georges
authors.initials: G
authors.lastname: Snounou
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D020128:Inhibitory Concentration 50; D016780:Malaria, Vivax / Q000469:parasitology; D008727:Methotrexate / Q000494:pharmacology*; D020125:Mutation, Missense; D010966:Plasmodium vivax / Q000187:drug effects* / Q000302:isolation & purification; D015800:Protozoan Proteins / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate; D011739:Pyrimethamine