Abstract
‘Malaria’ has been a threat to mankind for several centuries, and it remains a global burden affecting nearly half of the World’s Population. Malaria is caused by parasites of the genus Plasmodium, among which Plasmodium falciparum is the most lethal variant. Rapid emergence of drug resistance against frontline antimalarials and lack of vaccines has made it extremely imperative to identify new drugs with novel mechanisms of action. In an attempt to precisely expand this drive, we partnered with Medicines for Malaria Venture (MMV), to reappropriate and repurpose the “Pathogen Box” library (400 compounds) against Plasmodium falciparum asexual stage development. Egress of the malaria parasite from the host cell is a rate-limiting process contributing to parasite proliferation during the infectious cycle. This process is amenable to chemical interferences, thus we adopted a systematic, cellular phenotype-based antimalarial screening strategy to facilitate the identification of specific blockers of late-stage intraerythrocytic development. We identified 12 compounds that abrogated late-stage parasite development and stage transition. Further, we elucidate the mechanism of action (MOA) and, identified cellular targets for selected compounds by employing multi-omics approaches involving cell biomechanics, transcriptomics and, proteomics.. These findings open up the possibility of exploiting and repurposing these compounds for therapeutic development targeting late-stage development and egress against the new forms of drug-resistant malaria that are rapidly spreading across the developing world.