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Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies

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  • M. Isabel Veiga

    (Columbia University Medical Center
    Life and Health Sciences Research Institute (ICVS), School of Health Sciences and ICVS/3B’s—PT Government Associate Laboratory, University of Minho)

  • Satish K. Dhingra

    (Columbia University Medical Center)

  • Philipp P. Henrich

    (Columbia University Medical Center)

  • Judith Straimer

    (Columbia University Medical Center)

  • Nina Gnädig

    (Columbia University Medical Center)

  • Anne-Catrin Uhlemann

    (Columbia University Medical Center)

  • Rowena E. Martin

    (Research School of Biology, Linnaeus Way, The Australian National University)

  • Adele M. Lehane

    (Columbia University Medical Center
    Research School of Biology, Linnaeus Way, The Australian National University)

  • David A. Fidock

    (Columbia University Medical Center
    Columbia University Medical Center)

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.

Suggested Citation

  • M. Isabel Veiga & Satish K. Dhingra & Philipp P. Henrich & Judith Straimer & Nina Gnädig & Anne-Catrin Uhlemann & Rowena E. Martin & Adele M. Lehane & David A. Fidock, 2016. "Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11553
    DOI: 10.1038/ncomms11553
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    Cited by:

    1. Ruixue Xu & Lirong Lin & Zhiwei Jiao & Rui Liang & Yazhen Guo & Yixin Zhang & Xiaoxu Shang & Yuezhou Wang & Xu Wang & Luming Yao & Shengfa Liu & Xianming Deng & Jing Yuan & Xin-zhuan Su & Jian Li, 2024. "Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Tran Dang Nguyen & Bo Gao & Chanaki Amaratunga & Mehul Dhorda & Thu Nguyen-Anh Tran & Nicholas J. White & Arjen M. Dondorp & Maciej F. Boni & Ricardo Aguas, 2023. "Preventing antimalarial drug resistance with triple artemisinin-based combination therapies," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Aurel Holzschuh & Anita Lerch & Inna Gerlovina & Bakar S. Fakih & Abdul-wahid H. Al-mafazy & Erik J. Reaves & Abdullah Ali & Faiza Abbas & Mohamed Haji Ali & Mohamed Ali Ali & Manuel W. Hetzel & Joshu, 2023. "Multiplexed ddPCR-amplicon sequencing reveals isolated Plasmodium falciparum populations amenable to local elimination in Zanzibar, Tanzania," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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