Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies
Year: 2016
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms11553
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Role of pfcrt in chloroquine resistance in P. falciparum, CONTRIBUTION OF DRUG TRANSPORTER GENES TO THE EMERGENCE OF MULTI- AND EXTREMELY-DRUG RESISTANT PATHOGENS, Understanding how to combat drug resistance in the malaria parasite: Examination of two proteins that are key to the parasite’s ability to evade the toxic effects of antimalarial drugs, Factors influencing the susceptibility of the human malaria parasite to antimalarial drugs, G9000009225, G9000077734, Defining the Role of PfCRT and PfMDR1 as Pleiotropic Mediators of Plasmodium falciparum Multidrug Resistance, Elucidating the molecular basis of piperaquine resistance in Plasmodium falciparum, Defining P. falciparum resistance to artemisinin-based combination therapies
OpenAlex ID: W2397788564