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A broad analysis of resistance development in the malaria parasite

Author

Listed:
  • Victoria C. Corey

    (School of Medicine, University of California San Diego)

  • Amanda K. Lukens

    (Harvard T.H. Chan School of Public Health
    Infectious Disease Program, The Broad Institute)

  • Eva S. Istvan

    (Washington University School of Medicine)

  • Marcus C. S. Lee

    (Columbia University College of Physicians and Surgeons)

  • Virginia Franco

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Pamela Magistrado

    (Harvard T.H. Chan School of Public Health)

  • Olivia Coburn-Flynn

    (Columbia University College of Physicians and Surgeons)

  • Tomoyo Sakata-Kato

    (Harvard T.H. Chan School of Public Health)

  • Olivia Fuchs

    (School of Medicine, University of California San Diego)

  • Nina F. Gnädig

    (Columbia University College of Physicians and Surgeons)

  • Greg Goldgof

    (School of Medicine, University of California San Diego)

  • Maria Linares

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Maria G. Gomez-Lorenzo

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Cristina De Cózar

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Maria Jose Lafuente-Monasterio

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Sara Prats

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Stephan Meister

    (School of Medicine, University of California San Diego)

  • Olga Tanaseichuk

    (The Genomics Institute of the Novartis Research Foundation)

  • Melanie Wree

    (School of Medicine, University of California San Diego)

  • Yingyao Zhou

    (The Genomics Institute of the Novartis Research Foundation)

  • Paul A. Willis

    (Medicines for Malaria Venture)

  • Francisco-Javier Gamo

    (Tres Cantos Medicines Development Campus, Malaria DPU, GlaxoSmithKline)

  • Daniel E. Goldberg

    (Washington University School of Medicine)

  • David A. Fidock

    (Columbia University College of Physicians and Surgeons)

  • Dyann F. Wirth

    (Harvard T.H. Chan School of Public Health
    Infectious Disease Program, The Broad Institute)

  • Elizabeth A. Winzeler

    (School of Medicine, University of California San Diego)

Abstract

Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.

Suggested Citation

  • Victoria C. Corey & Amanda K. Lukens & Eva S. Istvan & Marcus C. S. Lee & Virginia Franco & Pamela Magistrado & Olivia Coburn-Flynn & Tomoyo Sakata-Kato & Olivia Fuchs & Nina F. Gnädig & Greg Goldgof , 2016. "A broad analysis of resistance development in the malaria parasite," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11901
    DOI: 10.1038/ncomms11901
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    Cited by:

    1. Selina Bopp & Charisse Flerida A. Pasaje & Robert L. Summers & Pamela Magistrado-Coxen & Kyra A. Schindler & Victoriano Corpas-Lopez & Tomas Yeo & Sachel Mok & Sumanta Dey & Sebastian Smick & Armiyaw , 2023. "Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Krittikorn Kümpornsin & Theerarat Kochakarn & Tomas Yeo & John Okombo & Madeline R. Luth & Johanna Hoshizaki & Mukul Rawat & Richard D. Pearson & Kyra A. Schindler & Sachel Mok & Heekuk Park & Anne-Ca, 2023. "Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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