1. Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites.
- Author
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Bates SJ, Winstanley PA, Watkins WM, Alloueche A, Bwika J, Happi TC, Kremsner PG, Kublin JG, Premji Z, and Sibley CH
- Subjects
- Alleles, Amino Acid Substitution, Animals, Antimalarials pharmacology, Dapsone pharmacology, Dapsone therapeutic use, Gabon, Humans, Kenya, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Malawi, Molecular Epidemiology, Mutation, Missense, Nigeria, Parasitic Sensitivity Tests, Plasmodium falciparum enzymology, Plasmodium falciparum isolation & purification, Point Mutation, Proguanil pharmacology, Proguanil therapeutic use, Sulfadoxine pharmacology, Tanzania, Drug Resistance genetics, Genes, Protozoan, Plasmodium falciparum drug effects, Plasmodium falciparum genetics, Proguanil analogs & derivatives, Pyrimethamine pharmacology, Tetrahydrofolate Dehydrogenase genetics
- Abstract
In eastern and southern Africa, there has been a rapid increase in the prevalence of alleles with mutations in the Plasmodium falciparum dihydrofolate reductase gene (dhfr) associated with increased risk of clinical failure of sulfadoxine-pyrimethamine (S/P). Molecular methods for surveillance of these mutations are now widespread, but the usual analysis detects only the most prevalent allele in a polyclonal sample. We used a yeast-expression system to identify rare, highly pyrimethamine-resistant alleles of dhfr in isolates from 5 African countries--Kenya, Tanzania, Malawi, Gabon, and Nigeria. Only the isolates from Nigeria yielded significant numbers of novel resistant alleles, and only 1 of the alleles from any location showed a >3-fold increase in resistance to S/P or to chlorproguanil-dapsone. Overall, these results suggest that dhfr alleles that confer high levels of resistance to antifolates are rare, even in eastern and southern Africa, where pyrimethamine has been intensively used.
- Published
- 2004
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