title: Plasmodium falciparum strains harboring dihydrofolate reductase with the I164L mutation are absent in Malawi and Zambia even under antifolate drug pressure.
abstract: The Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme is the target of pyrimethamine, a component of the antimalarial pyrimethamine-sulfadoxine. Resistance to this drug is associated primarily with mutations in the Pfdhfr gene. The I164L mutant allele is of particular interest, because strains possessing this mutation are highly resistant to pyrimethamine and to chlorproguanil, a component of chlorproguanil-dapsone. A recent study from Malawi reported this mutation at a prevalence of 4.7% in parasites from human immunodeficiency virus-positive pregnant women by using a real-time PCR method. These observations have huge implications for the use of pyrimethamine-sulfadoxine, chlorproguanil-dapsone, and future antifolate-artemisinin combinations in Africa. It was imperative that this finding be rigorously tested. We identified a number of critical limitations in the original genotyping strategy. Using a refined and validated real-time PCR strategy, we report here that this mutation was absent in 158 isolates from Malawi and 42 isolates from Zambia collected between 2003 and 2005.
authors: Department of Pharmacology and Therapeutics, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool, United Kingdom.
authors: Edwin
authors: E
authors: Ochong
authors: David J
authors: DJ
authors: Bell
authors: David J
authors: DJ
authors: Johnson
authors: Umberto
authors: U
authors: D'Alessandro
authors: Modest
authors: M
authors: Mulenga
authors: Sant
authors: S
authors: Muangnoicharoen
authors: Jean-Pierre
authors: JP
authors: Van Geertruyden
authors: Peter A
authors: PA
authors: Winstanley
authors: Patrick G
authors: PG
authors: Bray
authors: Stephen A
authors: SA
authors: Ward
authors: Andrew
authors: A
authors: Owen
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001483:Base Sequence; D002675:Child, Preschool; D017931:DNA Primers / Q000235:genetics; D016054:DNA, Protozoan / Q000032:analysis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005493:Folic Acid Antagonists / Q000494:pharmacology; D005787:Gene Frequency; D017125:Genes, Protozoan; D015658:HIV Infections / Q000150:complications; D006801:Humans; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy* / Q000469:parasitology*; D008295:Malawi; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000188:drug therapy / Q000469:parasitology; D011739:Pyrimethamine / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013785:Thailand; D015024:Zambia
chemical_list: D000962:Antimalarials; D017931:DNA Primers; D016054:DNA, Protozoan; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D011739:Pyrimethamine