The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin.
Although chloroquine-resistance (CQR) in Plasmodium falciparum is increasing and resistance to other blood schizonticidal anti-malarials has been reported, the molecular basis remains unclear. In this study fresh field isolates were obtained from The Gambia, an area of emerging CQR and tested for sensitivity to the anti-malarial drugs mefloquine, halofantrine, artemisinin, dihydroartemisinin, chloroquine and quinine. Sequence polymorphisms in the pfmdr1 gene and size polymorphisms in the cg2 gene were assessed using PCR-based systems. A strong association was observed between the presence of the tyr-86 allele of pfmdr1 and increased sensitivity to mefloquine and halofantrine, as well as the structurally unrelated drugs artemisinin and dihydroartemisinin. A weaker association was found between the presence of tyr-86 and increased resistance to chloroquine and quinine. The cg2 Dd2-like omega repeat size polymorphism was associated with increased resistance to chloroquine and increased sensitivity to mefloquine and halofantrine. An intragenic association was also found between a polymorphism in the polyasparagine linker region of pfmdr1 and the tyr-86 allele, which may be due to genetic hitchhiking, indicative of recent selection by chloroquine. Our data support a hypothesis where the pfmdr1 gene confers a true multidrug resistance phenotype which is lost by mutation.
Duraisingh
M T
MT
London School of Hygiene and Tropical Medicine, Keppel Street, London, UK.
Jones
P
P
Sambou
I
I
von Seidlein
L
L
Pinder
M
M
Warhurst
D C
DC
D018528:ATP-Binding Cassette Transporters; D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D015767:Mefloquine / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics*; D012717:Sesquiterpenes / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014443:Tyrosine / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D037621:Artemisinins; C109422:CG2 protein, Plasmodium falciparum; D015800:Protozoan Proteins; D012717:Sesquiterpenes; C059987:mdr gene protein, Plasmodium; D014443:Tyrosine; C031327:artemisinin; D013762:Tetrahydrofolate Dehydrogenase; D015767:Mefloquine