Targeting Host Metabolic Niche to Kill Malaria Parasites

Malaria remains a global health challenge, exacerbated by artemisinin resistance. Inspired by our recent study targeting aberrant cancer heme metabolism, we propose a novel "bait-and-kill" strategy, focusing on the unique metabolic vulnerability of infected Red Blood Cells (iRBCs) to destroy host niche. We exploit three key factors: 1) mature RBCs inherently possess a truncated heme biosynthesis pathway capable of accumulating heme intermediates, i.e ., porphyrins, 2) Uninfected RBCs exhibit impermeability to the heme precursor ALA (Aminolaevulinic acid), while infected RBCs demonstrate increased permeability, and 3) heme/porphyrin mediated activation of artemisinin has been established as the primary mechanism of action for their antimalarial activity. Utilizing the heightened membrane permeability of iRBCs, we employ the heme precursor ALA as “bait”, inducing heme intermediates accumulation. This synergizes with artemisinin, acting as the 'kill' agent, to effectively eradicate parasites. Uninfected RBCs do not uptake ALA, avoiding collateral damage. We present experimental characterization of drug-drug synergy in a malaria liver stage host cell line and successful elimination of artemisinin-resistant parasites during the blood stage, particularly parasites from the Great Mekong sub-region, a hotspot for antimalarial drug resistance. Leveraging safe drugs like ALA and artemisinin, tested globally, this synergistic strategy holds promise for large-scale deployment in malaria control.