Advancing (-)-Premarineosin A as a Potent Antimalarial Therapeutic via Metabolic Engineering and Late-Stage Derivatization

Despite modern preventative and curative efforts, malaria has remained a major global health crisis. In 2023 alone, malaria was responsible for an estimated 263 million cases and 597,000 deaths. To complicate this issue, the causative Plasmodium parasites are becoming more resistant to available therapeutics, making it difficult to treat and prevent disease progression. Hence, the discovery of new antimalarial drugs is crucial to mitigating this crisis. One promising contender is the natural product premarineosin A, an intermediate of the marineosin biosynthetic pathway that exhibits potent and selective antimalarial activity against both chloroquine-sensitive and multi-drug-resistant Plasmodium strains. However, its complex chemical structure and low production titers have prevented further exploration. To improve access to this promising metabolite, we identified a biosynthetic gene cluster for (-)-premarineosin A production in Streptomyces eitanensis. Metabolic engineering approaches increased production from trace levels to nearly 35 mg/L, which enabled semi-synthetic and biocatalytic derivatization of the (-)-premarineosin A scaffold. Late-stage C-H bromination of the B-ring resulted in a highly potent (EC ₅₀ < 5 nM) antimalarial compound with low cytotoxicity. These findings report progress toward the sustainable access of (-)-premarineosin A and the first structure-activity relationship study for this unique scaffold in the search for improved antimalarial therapeutics.