In vivo selection for a specific genotype of dihydropteroate synthetase of Plasmodium falciparum by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment.
Plasmodium falciparum present in blood samples collected before and 3 weeks after treatment with either pyrimethamine-sulfadoxine or chlorproguanil-dapsone was analyzed for variants of the genes coding for the target enzymes of antifolate drugs, dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). Fragments of the genes were amplified by polymerase chain reactions, and variants were identified by specific restriction endonuclease digestion. Treatment with either drug combination selected for the variants Ile51, Arg59, and Asn108 of DHFR, which have been associated with in vitro resistance to pyrimethamine and cycloguanil. The genotype Ser436, Gly437, and Glu540 of DHPS was selected by pyrimethamine-sulfadoxine but not chlorproguanil-dapsone treatment, showing that a combination of these three variants is important for in vivo resistance to sulfadoxine in the area studied.
Curtis
J
J
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom. j.curtis@lshtm.ac.uk
Duraisingh
M T
MT
Warhurst
D C
DC
D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D001120:Arginine; D001216:Asparagine; D002648:Child; D003622:Dapsone / Q000627:therapeutic use*; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004359:Drug Therapy, Combination; D017125:Genes, Protozoan; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007532:Isoleucine; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D002727:Proguanil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*
D000962:Antimalarials; D007532:Isoleucine; D001216:Asparagine; D013413:Sulfadoxine; C007030:chlorproguanil; D003622:Dapsone; D001120:Arginine; D004094:Dihydropteroate Synthase; D002727:Proguanil; D011739:Pyrimethamine