title: Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites.
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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7730, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bates
authors.forename: Peter A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: William M
authors.initials: WM
authors.lastname: Watkins
authors.forename: Ali
authors.initials: A
authors.lastname: Alloueche
authors.forename: Juma
authors.initials: J
authors.lastname: Bwika
authors.forename: T Christian
authors.initials: TC
authors.lastname: Happi
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
authors.forename: James G
authors.initials: JG
authors.lastname: Kublin
authors.forename: Zul
authors.initials: Z
authors.lastname: Premji
authors.forename: Carol Hopkins
authors.initials: CH
authors.lastname: Sibley
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D003622:Dapsone / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics*; D005681:Gabon; D017125:Genes, Protozoan; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008295:Malawi; D017720:Molecular Epidemiology; D020125:Mutation, Missense; D009549:Nigeria; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D017354:Point Mutation; D002727:Proguanil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011739:Pyrimethamine / Q000494:pharmacology*; D013413:Sulfadoxine / Q000494:pharmacology; D013636:Tanzania; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D000962:Antimalarials; D013413:Sulfadoxine; C007030:chlorproguanil; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D011739:Pyrimethamine