title: Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies.
abstract: Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.|Life and Health Sciences Research Institute (ICVS), School of Health Sciences and ICVS/3B's-PT Government Associate Laboratory, University of Minho, Gualtar Campus, 4710-057 Braga, Portugal.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Veiga
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Dhingra
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Philipp P
authors.initials: PP
authors.lastname: Henrich
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Straimer
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Gnädig
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, Box 82, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: Anne-Catrin
authors.initials: AC
authors.lastname: Uhlemann
authors.affiliation: Research School of Biology, Linnaeus Way, The Australian National University, Acton Australian Capital Territory 2601, Australia.
authors.forename: Rowena E
authors.initials: RE
authors.lastname: Martin
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.|Research School of Biology, Linnaeus Way, The Australian National University, Acton Australian Capital Territory 2601, Australia.
authors.forename: Adele M
authors.initials: AM
authors.lastname: Lehane
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.|Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, Box 82, 630 West 168th Street, New York, New York 10032, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
mesh_terms: D000962:Antimalarials; D037621:Artemisinins; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004359:Drug Therapy, Combination; D005843:Geography; D006239:Haplotypes; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D010963:Plasmodium falciparum / Q000235:genetics*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C031327:artemisinin