Metabolic engineering and late-stage functionalization expand the chemical space of the antimalarial premarineosin A
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 its 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 170-fold. Sustainable production of (-)-premarineosin A enabled a unique semi-synthetic and biocatalytic derivatization campaign. In this structure-activity relationship study of premarineosin A, we accessed a suite of analogs, including a C12-brominated derivative with nanomolar potency (EC<sub>50</sub> < 5 nM). This work establishes (-)-premarineosin A as a tractable and evolvable antimalarial scaffold, demonstrating how chemical biology approaches can unlock structural and pharmacological space from complex microbial metabolites.
Authors
- Natalia Harris
- Awet Alem Teklemichael
- Harrison M. Snodgrass (ORCID: https://orcid.org/0000-0002-0480-2022)
- Erin Oliphant (ORCID: https://orcid.org/0000-0002-7860-4889)
- David H. Sherman (ORCID: https://orcid.org/0000-0001-8334-3647)
- Jared C. Lewis (ORCID: https://orcid.org/0000-0003-2800-8330)
- Filipa Pereira (ORCID: https://orcid.org/0000-0002-0557-8480)
- Patricia Dranchak (ORCID: https://orcid.org/0000-0002-1349-4885)
- Morgan McCauley (ORCID: https://orcid.org/0000-0002-8646-5401)
- Fengrui Qu (ORCID: https://orcid.org/0000-0002-9975-2573)
- Katherine L. Lev (ORCID: https://orcid.org/0000-0002-8612-0972)
- Brian J. Curtis (ORCID: https://orcid.org/0000-0001-7503-3403)
- Xin‐zhuan Su (ORCID: https://orcid.org/0000-0003-3246-3248)
- Christina M. McBride (ORCID: https://orcid.org/0000-0001-9487-1525)
- James Inglese (ORCID: https://orcid.org/0000-0002-7332-5717)
- S. Amin
- Linnea Verhey-Henke
Institutions
- University of Michigan (US)
- National Human Genome Research Institute (US)
- Michigan Medicine (US)
- Indiana University Bloomington (US)
- National Institute of Allergy and Infectious Diseases (US)
- National Center for Advancing Translational Sciences (US)
Publication Details
- Journal
- Communications Chemistry
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1038/s42004-025-01779-6
- Primary Topic
- Microbial Natural Products and Biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- National Center for Advancing Translational Sciences
- NHLBI Division of Intramural Research