Discovery of an antimalarial compound, burnettiene A, with a multidrug-sensitive Saccharomyces cerevisiaescreening system based on mitochondrial function inhibitory activity

In this paper, we describe our discovery of burnettiene A (1) as an antimalarial compound from the culture broth of Lecanicillium primulinum(current name: Flavocillium primulinum) FKI-6715 strain utilizing our original multidrug-sensitive yeast system. This polyene-decalin polyketide natural product was originally isolated as an antifungal active compound from Aspergillus burnettii. However, the antifungal activity of 1has been revealed in only one fungal species, and the mechanism of action of 1remains unknown. After the validation of mitochondrial function inhibitory of 1, we envisioned a new antimalarial drug discovery platform based on mitochondrial function inhibitory activity. We evaluated antimalarial activity and 1showed antimalarial activity against Plasmodium falciparumFCR3 (chloroquine sensitive) and the K1 strain (chloroquine resistant). Our study revealed the utility of our original screening system based on a multidrug-sensitive yeast and mitochondrial function inhibitory activity for the discovery of new antimalarial drug candidates.Graphical AbstractDiscovery of burnettiene A (1) as an antimalarial compound A.