Achieving the goal of malaria elimination is vitally dependent on identifying validated drug targets that are active across all stages of the Plasmodium lifecycle. Here, we identify phosphatidylinositol-4 kinase (PfPI4K) as the target of the imidazopyrazines, a novel antimalarial compound class that potently inhibits the intracellular development of multiple Plasmodium species at each stage of infection of the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in several rodent malaria models. These compounds are also active against blood-stage field isolates of the major human malaria pathogens, P. falciparum and P. vivax, and inhibit liver stage hypnozoites in the human and simian parasite P. cynomolgi. Evolved resistance, full genome-scanning and genome editing experiments in intra-erythrocytic stages as well as biochemical data, show that imidazopyrazines exert their potent antimalarial activity through interaction with the ATP-binding pocket of the lipid kinase. Inhibition of PfPI4K, alters the intracellular distribution of phosphatidylinositol-4 phosphate, the PI4K product, and interferes with cytokinesis via a Rab11A-dependent pathway. Collectively, our data define PfPI4K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify antimalarial drugs with an ideal pharmacological profile for the prevention, treatment and elimination of malaria.
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