title: Reduced impact of pyrimethamine drug pressure on Plasmodium malariae dihydrofolate reductase gene.
abstract: Molecular investigations performed following the emergence of sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum have allowed the identification of the dihydrofolate reductase (DHFR) enzyme as the target of pyrimethamine. Although clinical cases of Plasmodium malariae are not usually treated with antifolate therapy, incorrect diagnosis and the high frequency of undetected mixed infections has probably exposed non-P. falciparum parasites to antifolate therapy in many areas. In this context, we aimed to assess the worldwide genetic diversity of the P. malariae dhfr gene in 123 samples collected in Africa and Asia, areas with different histories of SP use. Among the 10 polymorphic sites found, we have observed 7 new mutations (K55E, S58R, S59A, F168S, N194S, D207G, and T221A), which led us to describe 6 new DHFR proteins. All isolates from African countries were classified as wild type, while new mutations and haplotypes were recognized as exclusive to Madagascar (except for the double mutations at nucleotides 341 and 342 [S114N] found in one Cambodian isolate). Among these nonsynonymous mutations, two were likely related to pyrimethamine resistance: S58R (corresponding to C59R in P. falciparum and S58R in Plasmodium vivax; observed in one Malagasy sample) and S114N (corresponding to S108N in P. falciparum and S117N in P. vivax; observed in three Cambodian samples).
authors: Unité d'Epidémiologie Moléculaire du Paludisme, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors: Nimol
authors: N
authors: Khim
authors: Saorin
authors: S
authors: Kim
authors: Christiane
authors: C
authors: Bouchier
authors: Magali
authors: M
authors: Tichit
authors: Frédéric
authors: F
authors: Ariey
authors: Thierry
authors: T
authors: Fandeur
authors: Pheaktra
authors: P
authors: Chim
authors: Sopheakvatey
authors: S
authors: Ke
authors: Sarorn
authors: S
authors: Sum
authors: Somnang
authors: S
authors: Man
authors: Arsène
authors: A
authors: Ratsimbasoa
authors: Rémy
authors: R
authors: Durand
authors: Didier
authors: D
authors: Ménard
mesh_terms: D000349:Africa; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002160:Cambodia; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008270:Madagascar; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D009154:Mutation / Q000187:drug effects*; D021261:Parasitic Sensitivity Tests; D010965:Plasmodium malariae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D011739:Pyrimethamine / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000235:genetics
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine