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<p>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 <i>Streptomyces eitanensis</i>, 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> &lt; 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月5日

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  • 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

摘要

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.