Rare, Highly Pyrimethamine-Resistant Alleles of the Plasmodium falciparum Dihydrofolate Reductase Gene from 5 African Sites

• Published in: The Journal of infectious diseases 2004-11, Vol.190 (10), p.1783-1792
• Main Authors: Bates, Sarah J., Winstanley, Peter A., Watkins, William M., Alloueche, Ali, Bwika, Juma, Happi, T. Christian, Kremsner, Peter G., Kublin, James G., Premji, Zul, Sibley, Carol Hopkins
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Substitution; Animals; Antimalarials; Antimalarials - pharmacology; Biological and medical sciences; Codons; Dapsone - pharmacology; Dapsone - therapeutic use; Drug Resistance - genetics; Folic acid antagonists; Fundamental and applied biological sciences. Psychology; Gabon; Genes, Protozoan; Genetic mutation; Genotypes; Humans; Infectious diseases; Inhibitory concentration 50; Kenya; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Malawi; Medical sciences; Microbiology; Molecular Epidemiology; Mutation, Missense; Nigeria; Parasites; Parasitic Sensitivity Tests; Parasitism; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - genetics; Plasmodium falciparum - isolation & purification; Point Mutation; Proguanil - analogs & derivatives; Proguanil - pharmacology; Proguanil - therapeutic use; Pyrimethamine - pharmacology; Sulfadoxine - pharmacology; Tanzania; Tetrahydrofolate Dehydrogenase - genetics; Yeasts
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/425078

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 yeastexpression 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.