title: Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum.
abstract: The declining efficacy of chloroquine and pyrimethamine/sulphadoxine in the treatment of human malaria has led to the use of newer antimalarials such as mefloquine and artemisinin. Sequence polymorphisms in the pfmdr1 gene, the gene encoding the plasmodial homologue of mammalian multidrug resistance transporters, have previously been linked to resistance to chloroquine in some, but not all, studies. In this study, we have used a genetic cross between the strains HB3 and 3D7 to study inheritance of sensitivity to the structurally unrelated drugs mefloquine and artemisinin, and to several other antimalarials. We find a complete allelic association between the HB3-like pfmdr1 allele and increased sensitivity to these drugs in the progeny. Different pfmdr1 sequence polymorphisms in other unrelated lines were also associated with increased sensitivity to these drugs. Our results indicate that the pfmdr1 gene is an important determinant of susceptibility to antimalarials, which has major implications for the future development of resistance.
authors.affiliation: London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Duraisingh
authors.forename: C
authors.initials: C
authors.lastname: Roper
authors.forename: D
authors.initials: D
authors.lastname: Walliker
authors.forename: D C
authors.initials: DC
authors.lastname: Warhurst
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins; D002478:Cells, Cultured; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology*; D016296:Mutagenesis; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D015800:Protozoan Proteins / Q000235:genetics*; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D037621:Artemisinins; D015800:Protozoan Proteins; D012717:Sesquiterpenes; C059987:mdr gene protein, Plasmodium; C031327:artemisinin; D015767:Mefloquine