Development of a yeast bioassay for the screening of anti-malarial compounds with artemisinin-like activities

Abstract

Artemisinin is currently the most effective drug to treat malaria. However, the molecular target of artemisinin has yet to be determined, and this has impeded the search and discovery for other drugs from this class. In the yeast Saccharomyces cerevisiae, NADH dehydrogenases, which are encoded by NDE1 and NDI1 genes, were implicated as potential drug targets. A bioassay to screen for compounds with artemisinin-like activities was designed based on this hypothesis. Both the NDE1 and NDI1 genes were deleted from a wild type yeast strain to generate yeast mutants deficient in NADH dehydrogenase enzymes. Loss of NDE1 in yeast increased resistance towards artemisinin, and Δnde1 mutants were able to tolerate concentrations of artemisinin up to 12 μM. Compared to this, the wild type rapidly died in the presence of artemisinin. The Δndi1 mutant was, however, unable to grow on media without a fermentable carbon source.