title: Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum.
abstract: Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance; Pgh1 has also been implicated in resistance to mefloquine and halofantrine. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: M B
authors.initials: MB
authors.lastname: Reed
authors.forename: K J
authors.initials: KJ
authors.lastname: Saliba
authors.forename: S R
authors.initials: SR
authors.lastname: Caruana
authors.forename: K
authors.initials: K
authors.lastname: Kirk
authors.forename: A F
authors.initials: AF
authors.lastname: Cowman
mesh_terms: D018528:ATP-Binding Cassette Transporters; D019943:Amino Acid Substitution; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins; D002738:Chloroquine / Q000494:pharmacology; D003001:Cloning, Molecular; D004351:Drug Resistance; D015767:Mefloquine / Q000494:pharmacology; D009154:Mutation; D010616:Phenanthrenes / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology*; D011803:Quinine / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D037621:Artemisinins; D010616:Phenanthrenes; D015800:Protozoan Proteins; D012717:Sesquiterpenes; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine; C031327:artemisinin; D011803:Quinine; D014700:Verapamil; C023768:halofantrine; D015767:Mefloquine