Abstract
Malaria is a century-old infectious disease, which remains a major global burden affecting more than half of the world’s population. Plasmodium, the causative agent of this disease, has acquired resistance against all the currently available frontline antimalarials including artemisinin and combinations thereof. Widespread resistance and lack of commercially available vaccines necessitate a compelling need to identify novel drug candidates with new mechanisms of action. Host invasion and parasite-exit (egress) represent unique rate-limiting steps during the infectious cycle that are proven amenable for chemical interference. We leveraged on the “Malaria Box” chemical library made available through Medicines for Malaria Venture (MMV) as a starting point for discovering small molecules that arrest egress and invasion. Towards this, new phenotype-based assays were developed, standardized and applied to identify highly-potent egress inhibitors belonging to novel chemical classes. We then employed multi-omics approaches (transcriptomics, proteomics, and cell-biomechanics) to elucidate their specific mechanisms of action thereby confirming the cellular and molecular changes associated with small molecule-mediated egress inhibition. These findings represent a significant advancement in our efforts to explore egress inhibition as an avenue for therapeutic development against new variants of malaria that are rapidly spreading across the developing world.