Polymorphisms in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes of Plasmodium falciparum and in vivo resistance to sulphadoxine/pyrimethamine in isolates from Tanzania.
The efficacy of sulphadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of mutations associated with the active site sequence in the Plasmodium falciparum genes coding for dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) is associated with in vitro resistance to pyrimethamine and sulphadoxine. This study investigates the occurrence of these mutations in infected blood samples taken from Tanzanian children before treatment with S/P and their relationship to parasite breakthrough by day 7. The results show that alleles of DHPS (436-alanine, 437-alanine and 540-lysine) were significantly reduced in prevalence on day 7 after S/P treatment. In this area, a DHPS with 436-serine, 437-glycine and 540-glutamate appears to play a major role in resistance to S/P in vivo. Evidence for the influence of mutations in the DHFR gene in this investigation is not clear, probably because of the high prevalence of 'resistance-related' mutations at day 0 in the local parasite population. For apparently the same reason, it was not possible to show a statistical association between S/P resistance and the presence of particular polymorphisms in the DHFR and DHPS genes before treatment.
Jelinek
T
T
London School of Hygiene and Tropical Medicine, Department of Medical Parasitology, UK. jelinek@lrz.uni-muenchen.de
Rønn
A M
AM
Lemnge
M M
MM
Curtis
J
J
Mhina
J
J
Duraisingh
M T
MT
Bygbjerg
I C
IC
Warhurst
D C
DC
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D004094:Dihydropteroate Synthase / Q000097:blood / Q000235:genetics*; D004352:Drug Resistance, Microbial; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*; D013636:Tanzania; D013762:Tetrahydrofolate Dehydrogenase / Q000097:blood / Q000235:genetics*
D000962:Antimalarials; D017931:DNA Primers; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine