Metabolic engineering and late-stage functionalization expand the chemical space of the antimalarial premarineosin A

Christina M McBride; Morgan McCauley; Natalia R Harris; Sahar Amin; Brian J Curtis; Linnea Verhey-Henke; Awet A Teklemichael; Erin N Oliphant; Patricia Dranchak; Katherine L Lev; Fengrui Qu; Harrison M Snodgrass; Jared C Lewis; James Inglese; Xin-Zhuan Su; Filipa Pereira; David H Sherman

doi:10.1038/s42004-025-01779-6

Metabolic engineering and late-stage functionalization expand the chemical space of the antimalarial premarineosin A

Commun Chem. 2025 Dec 5;8(1):391. doi: 10.1038/s42004-025-01779-6.

Authors

Christina M McBride^#^{1

2}, Morgan McCauley^#¹, Natalia R Harris^{1

3}, Sahar Amin^{1

4}, Brian J Curtis¹, Linnea Verhey-Henke¹, Awet A Teklemichael⁵, Erin N Oliphant⁶, Patricia Dranchak⁶, Katherine L Lev^{1

2}, Fengrui Qu⁷, Harrison M Snodgrass⁸, Jared C Lewis⁹, James Inglese^{6

10}, Xin-Zhuan Su⁵, Filipa Pereira^{11

12}, David H Sherman^{13

14

15

16}

Affiliations

¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
² Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
⁵ Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, USA.
⁶ National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, MD, USA.
⁷ Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
⁸ Department of Chemistry, Indiana University, Bloomington, IN, USA.
⁹ Department of Chemistry, Indiana University, Bloomington, IN, USA. jcl3@iu.edu.
¹⁰ Metabolic Medicine Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
¹¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. fpere@umich.edu.
¹² Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA. fpere@umich.edu.
¹³ Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.
¹⁴ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.
¹⁵ Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.
¹⁶ Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA. davidhs@umich.edu.

^# Contributed equally.

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 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 (EC₅₀ < 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.

Abstract

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