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

Xie Wah Audrey Chan, Carsten Wrenger, Katharina Stahl, Bärbel Bergmann, Markus Winterberg, Ingrid B. Müller () and Kevin J. Saliba ()
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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
Katharina Stahl: Bernhard Nocht Institute for Tropical Medicine
Bärbel Bergmann: 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
Kevin J. Saliba: Research School of Biology, College of Medicine, Biology and Environment, The Australian National University

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3060

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