Sensitivity to antifolates and genetic analysis of Plasmodium vivax isolates from Thailand.
We investigated the association between the Plasmodium vivax dihydrofolate reductase (Pvdhfrtas) and the P. vivax dihydropteroate synthase (Pvdhps) genotype and in vitro sensitivity to the antifolates pyrimethamine, WR99210, chlorcycloguanil, sulfadoxine, and dapsone. Drug responses of 32 P. vivax isolates were assessed in two in vitro systems: schizont maturation inhibition and a yeast expression system. The geometric mean of 50% inhibition concentration (IC(50)) values for pyrimethamine, chlorcycloguanil, WR99210, sulfadoxine, and dapsone were 85 +/- 88, 784 +/- 662, 95 +/- 87, 2,424 +/- 2,784, and 1,625 +/- 1,801 nM, respectively, for the schizont maturation assay. Five different Pvdhfr alleles and four Pvdhps alleles were observed: 26 of 32 quadruple mutant alleles of Pvdhfr (F57I,L/S58R/T61M/S117T), four triple mutants (S58R/T61M/S117T, K49C/S58R/S117N), and two double mutant isolates (S58R/S117N). All isolates carried Pvdhps 585V. Twenty four isolates carried double mutant Pvdhps (A383G/A553G), six an additional mutation, S382A,C/A383G/A553G, and two a single mutation, A383G. Increasing geometric mean IC(50) values were observed with increased number of Pvdhfr mutations from double to quadruple. Results suggest that quadruple mutant alleles confer decreased sensitivity to pyrimethamine but retain sensitivity to WR99210.
Rungsihirunrat
Kanchana
K
Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand.
Na-Bangchang
Kesara
K
Hawkins
Vivian N
VN
Mungthin
Mathirut
M
Sibley
Carol Hopkins
CH
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003001:Cloning, Molecular; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D016780:Malaria, Vivax / Q000469:parasitology*; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D013785:Thailand
D000962:Antimalarials; D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase