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.
Highlights
Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites
Recent advances in whole-genome sequencing and genome analysis, applied to thousands of P. falciparum genomes by the MalariaGEN consortium[8,29], permit a detailed investigation of PfMDR1 haplotypes across malaria-endemic regions of Southeast Asia and Africa
By analysing 2,512 parasite genomes made available by this consortium, we determined the frequencies of the four PfMDR1 haplotypes differing at residues 86 and 184 across multiple countries (Fig. 2 and Supplementary Table 1)
Summary
Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. 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. The major partner drugs are lumefantrine (LMF, which combined with artemether (ATM) constitutes the most widely used ACT), mefloquine (MFQ, paired with artesunate (AS)), amodiaquine (ADQ, paired with AS) and piperaquine (PPQ, combined with the active ART metabolite dihydroartemisinin (DHA)) These drugs share certain chemical features such as the 4-aminoquinoline ring present in ADQ and PPQ (as well as chloroquine, CQ) or the arylaminoalcohol group present in LMF and MFQ (Fig. 1), and appear to interact with the parasite haem detoxification pathway[2].
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