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Chemical and genetic validation of thiamine utilization as an antimalarial drug target

Author

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  • Xie Wah Audrey Chan

    (Research School of Biology, College of Medicine, Biology and Environment, The Australian National University)

  • Carsten Wrenger

    (Bernhard Nocht Institute for Tropical Medicine
    Unit for Drug Discovery, Institute of Biomedical Science, University of São Paulo)

  • Katharina Stahl

    (Bernhard Nocht Institute for Tropical Medicine)

  • Bärbel Bergmann

    (Bernhard Nocht Institute for Tropical Medicine
    Laboratory Müller, Bernhard Nocht Institute for Tropical Medicine)

  • Markus Winterberg

    (Research School of Biology, College of Medicine, Biology and Environment, The Australian National University)

  • Ingrid B. Müller

    (Bernhard Nocht Institute for Tropical Medicine
    Laboratory Müller, Bernhard Nocht Institute for Tropical Medicine)

  • Kevin J. Saliba

    (Research School of Biology, College of Medicine, Biology and Environment, The Australian National University
    Medical School, College of Medicine, Biology and Environment, The Australian National University)

Abstract

Thiamine is metabolized into an essential cofactor for several enzymes. Here we show that oxythiamine, a thiamine analog, inhibits proliferation of the malaria parasite Plasmodium falciparum in vitro via a thiamine-related pathway and significantly reduces parasite growth in a mouse malaria model. Overexpression of thiamine pyrophosphokinase (the enzyme that converts thiamine into its active form, thiamine pyrophosphate) hypersensitizes parasites to oxythiamine by up to 1,700-fold, consistent with oxythiamine being a substrate for thiamine pyrophosphokinase and its conversion into an antimetabolite. We show that parasites overexpressing the thiamine pyrophosphate-dependent enzymes oxoglutarate dehydrogenase and pyruvate dehydrogenase are up to 15-fold more resistant to oxythiamine, consistent with the antimetabolite inactivating thiamine pyrophosphate-dependent enzymes. Our studies therefore validate thiamine utilization as an antimalarial drug target and demonstrate that a single antimalarial can simultaneously target several enzymes located within distinct organelles.

Suggested Citation

  • Xie Wah Audrey Chan & Carsten Wrenger & Katharina Stahl & Bärbel Bergmann & Markus Winterberg & Ingrid B. Müller & Kevin J. Saliba, 2013. "Chemical and genetic validation of thiamine utilization as an antimalarial drug target," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3060
    DOI: 10.1038/ncomms3060
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