Point mutations in the dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum and resistance to sulfadoxine-pyrimethamine in Sri Lanka.
Sulfadoxine-pyrimethamine (SP) is the second-line treatment for Plasmodium falciparum malaria in Sri Lanka. Resistance to SP is caused by point mutations in the dihydrofolate reductase (Pf-dhfr) and dihydropteroate synthase (Pf-dhps) genes of P. falciparum. We determined the genotype of Pf-dhfr and Pf-dhps and the clinical response to SP in 30 field isolates of P. falciparum from Sri Lanka. All patients treated with SP had an adequate clinical response. Eighty-five percent (23 of 27) of pure field isolates carried parasites with double mutant alleles of Pf-dhfr (C59R + S108N) and showed about 200-fold higher levels of resistance to pyrimethamine than the wild type in a yeast system. None of the isolates had either known or novel mutations at other positions in the dhfr domain. In contrast, 67% (20 of 30) of the isolates carried parasites that were wild type for Pf-dhps. In Sri Lanka, detection of the triple mutant allele of Pf-dhfr will require tracking mutations at codon 51.
Hapuarachchi
Hapuarachchige C
HC
Department of Parasitology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
Dayanath
Meegoda Y D
MY
Bandara
Kandeyaye Bandaralage A T
KB
Abeysundara
Sudusinghe
S
Abeyewickreme
Wimaladharma
W
de Silva
Nilanthi R
NR
Hunt
Sonia Y
SY
Sibley
Carol Hopkins
CH
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use*; D017931:DNA Primers; D004094:Dihydropteroate Synthase / Q000235:genetics; D004338:Drug Combinations; D018432:Drug Resistance, Multiple; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology* / Q000517:prevention & control*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011739:Pyrimethamine / Q000494:pharmacology / Q000627:therapeutic use*; D013188:Sri Lanka / Q000453:epidemiology; D013413:Sulfadoxine / Q000494:pharmacology / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D017211:Treatment Failure
D000962:Antimalarials; D017931:DNA Primers; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine