A kalihinol analog disrupts apicoplast function and vesicular trafficking in <i>P. falciparum</i> malaria
Zeinab Chahine, Steffen Abel, Thomas Hollin, Griffin L. Barnes, Jing-Gung Chung, Mary Elisabeth Daub, Isaline Renard, Jae‐Yeon Choi, Pratap Vydyam, Anasuya Pal, M. Alba-Argomaniz, Charles A.S. Banks, Jay S. Kirkwood, Anita Saraf, Isabel Camino, P. Castaneda, Mauro Cuevas, J. De Mercado-Arnanz, E. Fernandez-Alvaro, A. Garcia-Perez, Nuria Ibarz, S. Viera-Morilla, Jacques Prudhomme, Chester J. Joyner, Amy K. Bei, Laurence Florens, Choukri Ben Mamoun, Christopher D. Vanderwal, Karine G. Le Roch
Abstract
We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13 , which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.