Plasmodium falciparum: selection of serine 108 of dihydrofolate reductase during treatment of uncomplicated malaria with co-trimoxazole in Ugandan children.
In vivo testing for resistance of Plasmodium falciparum to co-trimoxazole (trimethoprim/sulfamethoxazole) was performed in Uganda in 41 children with uncomplicated malaria, and blood samples were screened before and after treatment for polymorphisms in the antifolate target genes for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). Selection towards a specific genotype at some codons of the DHFR and DHPS genes was observed in samples collected after exposure to co-trimoxazole drug pressure. The alleles 51-isoleucine, 59-arginine, and 108-serine of DHFR were significantly associated with clinical resistance, as was allele 581-alanine of DHPS. Resistance against antifolate combinations probably requires resistance-related polymorphisms in both the DHFR and the DHPS genes. In addition, it appears that the trimethoprim-resistant DHFR genotype differs from that for pyrimethamine at residue 108.
Jelinek
T
T
Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, United Kingdom.
Kilian
A H
AH
Curtis
J
J
Duraisingh
M T
MT
Kabagambe
G
G
von Sonnenburg
F
F
Warhurst
D C
DC
D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D001769:Blood / Q000469:parasitology; D002675:Child, Preschool; D017931:DNA Primers / Q000737:chemistry; D004262:DNA Restriction Enzymes / Q000737:chemistry; D016054:DNA, Protozoan / Q000737:chemistry; D004094:Dihydropteroate Synthase / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance; D004587:Electrophoresis, Agar Gel; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D010963:Plasmodium falciparum / Q000737:chemistry / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*; D014454:Uganda
D000962:Antimalarials; D017931:DNA Primers; D016054:DNA, Protozoan; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D004262:DNA Restriction Enzymes