Discovery of Sphaeriaurantins as Rapid-Acting Antiplasmodials with Dual Activity in Blood and Liver Stages
Chantal D. Bader, Jennifer E. Collins, Yuelan Li, Edward Kalkreuter, Jasveen Bhasin, Mariana Laureano De Souza, Raphaella A. Paes Lopez, Jin H. Jeon, Nonlawat Boonyalai, Chun Gui, Dong Yang, David A. Fidock, Marcus C. S. Lee, Elizabeth A. Winzeler, Debopam Chakrabarti, Ben ShenAbstract
The rapid emergence of resistance in the malaria-causing protozoan Plasmodium falciparum has heightened the demand for treatments with novel modes of action. Having evolved to produce a myriad of structurally diverse natural products (NPs) as defenses against soil-dwelling parasites including protozoa, Actinomycetota strains are a promising source for the discovery of NPs as antiplasmodial drug leads. Herein, the selective inhibition of P. falciparum is reported for five distinct NP families from Actinomycetota, including an unprecedented family of glycosylated type II polyketides termed sphaeriaurantins (SPAs). The structures of SPAs were established through the combination of MS and NMR spectroscopic data analysis, derivatization and comparison of the deoxyhexose moieties to authentic standards, and quantum chemical calculations, including 1H and 13C NMR chemical shifts and electronic circular dichroism (ECD) spectra. The three isolated SPA congeners reveal that the characteristic pseudodimeric structure of the SPA family of NPs, likely introduced at a late stage of the SPA biosynthesis, is highly relevant for the observed low nanomolar activity. SPA A exhibits a rapid killing profile, with activities across all intraerythrocytic stages, and potent liver stage efficacy, as well as a low propensity for resistance development. Taken together, these results suggest a mode of action that most likely is distinct from the existing antimalarials, supporting SPA A as a promising antimalarial drug lead for further development.