title: Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization.
abstract: Sulfadoxine/pyrimethamine (Fansidar) is widely used in Africa for treating chloroquine-resistant falciparum malaria. To clarify how parasite resistance to this combination arises, various lines of Plasmodium falciparum were used to investigate the role of naturally occurring mutations in the target enzyme, dihydropteroate synthetase (DHPS), in the parasite response to sulfadoxine inhibition. An improved drug assay was employed to identify a clear correlation between sulfadoxine-resistance levels and the number of DHPS mutations. Moreover, tight linkage was observed between DHPS mutations and high-level resistance in the 16 progeny of a genetic cross between sulfadoxine-sensitive (HB3) and sulfadoxine-resistant (Dd2) parents. However, we also demonstrate a profound influence of exogenous folate on IC50 values, which, under physiological conditions, may have a major role in determining resistance levels. Importantly, this phenotype does not segregate with dhps genotypes in the cross, but shows complete linkage to the two alleles of the dihydrofolate reductase (dhfr) gene inherited from the parental lines. However, in unrelated lines, this folate effect correlates less well with DHFR sequence, indicating that the gene responsible may be closely linked to dhfr, rather than dhfr itself. These results have major implications for the acquisition of Fansidar resistance by malaria parasites.
authors.affiliation: Department of Biochemistry and Applied Molecular Biology, University of Manchester Institute of Science and Technology (UMIST), UK.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Read
authors.forename: P F
authors.initials: PF
authors.lastname: Sims
authors.forename: J E
authors.initials: JE
authors.lastname: Hyde
mesh_terms: D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004336:Drug Antagonism; D004338:Drug Combinations; D004352:Drug Resistance, Microbial / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology; D008040:Genetic Linkage; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008826:Microbial Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011739:Pyrimethamine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D013413:Sulfadoxine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine