Efficacy of the Antimalarial MMV390048 against Infection Reveals Phosphatidylinositol 4-Kinase as a Druggable Target for Babesiosis.

The present study aimed to evaluate the anti- effect of MMV390048, a drug that inhibits by targeting the phosphatidylinositol 4-kinase (PI4K). The half inhibitory concentration (IC) of MMV390048 against the growth of was 6.9 ± 0.9 μM. In immunocompetent mice, oral treatment with MMV390048 at a concentration of 20 mg/kg effectively inhibited the growth of B. microti (Peabody mjr strain). The peak parasitemia in the control group was 30.5%, whereas the peak parasitemia in the MMV390048-treated group was 3.4%. Meanwhile, MMV390048 also showed inhibition on the growth of (Australia strain), a highly pathogenic rodent species. All MMV390048-treated mice survived, whereas the mice in control group died within 10 days postinfection (DPI). The first 7-day administration of MMV390048 in B. microti-infected, severe combined immunodeficiency (SCID) mice delayed the rise of parasitemia by 26 days. Subsequently, a second 7-day administration was given upon recurrence. At 52 DPI, a parasite relapse (in 1 out of 5 mice) and a mutation in the B. microti PI4K L746S, a MMV390048 resistance-related gene, were detected. Although the radical cure of B. microti infection in immunocompromised host SCID mice was not achieved, results from this study showed that MMV390048 has excellent inhibitory effects on parasites, revealing a new treatment strategy for babesiosis: targeting the B. microti PI4K.