Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites.
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.
Bates
Sarah J
SJ
Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7730, USA.
Winstanley
Peter A
PA
Watkins
William M
WM
Alloueche
Ali
A
Bwika
Juma
J
Happi
T Christian
TC
Kremsner
Peter G
PG
Kublin
James G
JG
Premji
Zul
Z
Sibley
Carol Hopkins
CH
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*
D000962:Antimalarials; D013413:Sulfadoxine; C007030:chlorproguanil; D003622:Dapsone; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil; D011739:Pyrimethamine