A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking inP. falciparumMalaria

Abstract

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and-resistantP. falciparumstrains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective againstP. knowlesiandP. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses inP. falciparumrevealed that a mutation inPfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189in vitroandin vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.Editor’s SummaryHere we report the mode of action and mechanism of resistance of a pan-antimalarial agent, MED6-189, which disrupts apicoplast function and vesicular trafficking inP. falciparum.