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bioRxiv · 10.1101/2025.01.28.635342

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

McBride, C. M.·McCauley, M.·Harris, N. R.·Amin, S.·Verhey-Henke, L.·Teklemichael, A. A.·Oliphant, E. N.·Dranchak, P.·Curtis, B. J.·Lev, K. L.·Qu, F.·Snodgrass, H. M.·Lewis, J. C.·Inglese, J.·Su, X.-z.·Pereira, F.·Sherman, D. H.
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Abstract

Diversification of structurally complex natural products remains a key challenge in the discovery of next-generation therapeutics. Premarineosin A, a potent and selective antimalarial natural product, is a promising yet underexplored scaffold due to limited availability and synthetic complexity. In this work, we overcome both barriers by coupling metabolic engineering with late-stage derivatization, enabling the first systematic exploration of the premarineosin A scaffold. Rational engineering of Streptomyces eitanensis, encoding a (-)-premarineosin A biosynthetic gene cluster, increased titers over 200-fold. Sustainable production of (-)-premarineosin A enabled a unique semi-synthetic and biocatalytic derivatization campaign. In this first structure-activity relationship study of premarineosin A, we accessed a suite of novel analogs, including a C12-brominated derivative with nanomolar potency (EC50 < 5 nM). This work establishes (-)-premarineosin A as a tractable and evolvable antimalarial scaffold, demonstrating how chemical biology approaches can unlock new structural and pharmacological space from complex microbial metabolites.

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McBride, C. M., McCauley, M., Harris, N. R., Amin, S., Verhey-Henke, L., Teklemichael, A. A., Oliphant, E. N., Dranchak, P., Curtis, B. J., Lev, K. L., Qu, F., Snodgrass, H. M., Lewis, J. C., Inglese, J., Su, X.-z., Pereira, F., Sherman, D. H.. 2025-01-28. Advancing (-)-Premarineosin A as a Potent Antimalarial Therapeutic via Metabolic Engineering and Late-Stage Derivatization. https://doi.org/10.1101/2025.01.28.635342

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