Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b.

Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype.

A surface-display biohybrid approach to light-driven hydrogen production in air.

Solar-to-chemical production by artificial and bioinspired photosynthetic systems is of tremendous interest to help solve current global energy and environmental problems. We developed a bioinorganic hybrid system for photocatalytic hydrogen production under aerobic conditions by combining light-harvesting semiconductors, hydrogenase catalysis, and self-aggregation of whole bacterial cells. We induced hydrogen production via self-photosynthesis in engineered Escherichia coli cells, which were originally designed for bioremediation, with in situ biosynthesis of biocompatible cadmium sulfide nanoparticles using a surface-display system. We also introduced a biomimetic silica encapsulation strategy into the engineered E. coli cells, enabling this hybrid system to continuously produce hydrogen for 96 hours, even under natural aerobic conditions. This biohybrid catalytic approach may serve as a general strategy for solar-to-chemical production.