Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies
作者： M. Isabel Veiga , Satish K. Dhingra , Philipp P. Henrich , Judith Straimer , Nina Gnädig
DOI: 10.1038/NCOMMS11553
关键词:
摘要: 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 multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, demonstrate that widely prevalent N86Y mutation augments ACT partner amodiaquine former first-line agent chloroquine. In contrast, increases parasite susceptibility drugs lumefantrine mefloquine, active artemisinin metabolite dihydroartemisinin. The N86 plus Y184F isoform moderately reduces piperaquine potency strains expressing an Asian/African variant chloroquine PfCRT. Mutations both digestive vacuole-resident transporters are thought differentially regulate interactions with host haem, a product parasite-mediated haemoglobin degradation. Global mapping these mutations illustrates where different ACTs could be selectively deployed optimize treatment based regional differences haplotypes.
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