MED6-189: An effective Antimalarial Kalihinol Analog Targets Plasmodium falciparum Apicoplast and Membrane Biogenesis

Members of the Isocyanoterpene (ICT) family of sponge-derived natural products have been shown to have potent activity against the human malaria parasite Plasmodium falciparum; however, no front-runner drug-like candidates have been identified and their mechanism of action remain unknown heretofore. Here we report MED6-189, an analogue of the kalihinol subfamily of ICTs that demonstrates potent antimalarial activity both in vitro and in vivo. The compound is effective against drug-sensitive and -resistant P. falciparum strains and blocks both intraerythrocytic asexual replication and sexual differentiation. In vivo efficacy studies using a humanized mouse model of P. falciparum infection further confirmed the strong efficacy of the compound in animals with no apparent hemolytic activity nor other major findings of toxicity. The compound was also effective against P. knowlesi. Cell biological analyses revealed that the compound is targeted primarily to the parasite apicoplast and acts by inhibiting lipid biogenesis and trafficking. Consistent with this mode of action, genetic analyses in P. falciparum identified mutants with reduced susceptibility to the drug due to a mutation in the SEC13 gene encoding a component of the parasite secretory machinery. Using yeast as a model system we show that altered expression of the yeast Sec13 also affects susceptibility to MED6-189. The high potency of MED6-189 in vitro and in vivo, its broad range efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.