title: pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum.
abstract: The emergence and spread of multidrug resistant Plasmodium falciparum has severely limited the therapeutic options for the treatment of malaria. With ever-increasing failure rates associated with chloroquine or sulphadoxine-pyrimethamine treatment, attention has turned to the few alternatives, which include quinine and mefloquine. Here, we have investigated the role of pfmdr1 3' coding region point mutations in antimalarial drug susceptibility by allelic exchange in the GC03 and 3BA6 parasite lines. Results with pfmdr1-recombinant clones indicate a significant role for the N1042D mutation in contributing to resistance to quinine and its diastereomer quinidine. The triple mutations S1034C/N1042D/D1246Y, highly prevalent in South America, were also found to enhance parasite susceptibility to mefloquine, halofantrine and artemisinin. pfmdr1 3' mutations showed minimal effect on P. falciparum resistance to chloroquine or its metabolite mono-desethylchloroquine in these parasite lines, in contrast to previously published results obtained with 7G8 parasites. This study supports the hypothesis that pfmdr1 3' point mutations can significantly affect parasite susceptibility to a wide range of antimalarials in a strain-specific manner that depends on the parasite genetic background.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Amar Bir Singh
authors.initials: AB
authors.lastname: Sidhu
authors.forename: Stephanie Gaw
authors.initials: SG
authors.lastname: Valderramos
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D001216:Asparagine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D015767:Mefloquine / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017354:Point Mutation; D015800:Protozoan Proteins / Q000235:genetics*; D011803:Quinine / Q000494:pharmacology*; D012717:Sesquiterpenes / 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; D001224:Aspartic Acid; D001216:Asparagine; C031327:artemisinin; D011803:Quinine; C023768:halofantrine; D015767:Mefloquine