Conference Agenda

Malaria remains one of the most devastating infectious diseases globally. Resistance to frontline antimalarials continues to compromise control efforts, highlighting the urgent need for novel therapeutic strategies. We previously identified the strobilurin compound MMV1794211 as a highly potent antiplasmodial agent with low-picomolar activity against blood-stage Plasmodium falciparum. Biochemical and enzymatic analyses demonstrated that MMV1794211 targets Complex III of the parasite mitochondrial electron transport chain (mtETC), a clinically validated antimalarial target. Our recent structure-activity relationship studies have identified key chemical elements underlying its potency and enabled the synthesis of derivative compounds with favourable antiplasmodial activity and enhanced selectivity for parasites over human cells. In vitro evolution experiments generated parasites carrying a single mutation in cytochrome b conferring high-level resistance to MMV1794211. Drug sensitivity profiling of the mutant revealed pan-strobilurin resistance; however, no cross-resistance was observed with established antimalarials or other mtETC inhibitors currently under investigation. Ongoing work includes assessing the fitness costs associated with strobilurin-resistance mutations and developing derivative compounds that remain active in resistant parasites. Collectively, our study provides a comprehensive evaluation of strobilurins as a chemically distinct class of antiplasmodial agents and highlights their promise for future therapeutic development.