title: High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium falciparum in isolates from Tanzania without evidence of an association to clinical sulfadoxine/pyrimethamine resistance.
abstract: Recently the efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Tanzania has been seriously compromised by the development of resistance. The occurrence of active site mutations in the Plasmodium falciparum gene sequence coding for dihydrofolate reductase (DHFR) is known to confer resistance to pyrimethamine. 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 confirm the occurrence of one or more DHFR mutations in all the samples, but no relationship was found with the presence of parasites in the blood at day 7. The results suggest that alterations in the coding region for dihydropteroate synthetase (DHPS), the enzyme target for sulfadoxine, should be studied in order to predict resistance to the S/P combination. It has been proposed earlier that sulfadoxine could itself act on DHFR, because of a false dihydrofolate produced by drug metabolism through DHPS and dihydrofolate synthase. The results of this treatment study suggest that such a possibility is unlikely.
authors.affiliation: Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, United Kingdom. t.jelinek@lshtm.ac.uk
authors.forename: T
authors.initials: T
authors.lastname: Jelinek
authors.forename: A M
authors.initials: AM
authors.lastname: Rønn
authors.forename: J
authors.initials: J
authors.lastname: Curtis
authors.forename: M T
authors.initials: MT
authors.lastname: Duraisingh
authors.forename: M M
authors.initials: MM
authors.lastname: Lemnge
authors.forename: J
authors.initials: J
authors.lastname: Mhina
authors.forename: I C
authors.initials: IC
authors.lastname: Bygbjerg
authors.forename: D C
authors.initials: DC
authors.lastname: Warhurst
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D016054:DNA, Protozoan / Q000032:analysis; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D008297:Male; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification; D017354:Point Mutation; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*; D013636:Tanzania; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D000962:Antimalarials; D016054:DNA, Protozoan; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine