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<p>Small-molecule metabolites are key pharmaceutical resources embedded in complex organismal metabolomes. Scalable microbial production depends on metabolic activation capacity, which in turn requires efficient genetic variation. Structural variants (SVs), key drivers of phenotypic diversity, are pivotal for organism evolution, yet their highly efficient induction remains challenging. While DNA double-strand breaks (DSBs) facilitate SVs formation, existing mutagenesis technologies struggle to balance high DSB efficiency with cellular preservation, particularly in microbial strain improvement for metabolite production. Conventional irradiation methods suffer from low SVs induction rates, making strain enhancement a lengthy and labor-intensive process. Here, we systematically compare six irradiation technologies in <i>Streptomyces lividans</i> 1326 and identify high-energy pulsed electron beams (HEPE) as an approach which effectively induces strong DSBs while preserving cellular integrity. This results in extensive SVs that reshape genome sequences and 3D chromatin structure, leading to activation of secondary metabolite production. By integrating HEPE with high-throughput metabolomics (HEPE-HiTMS), we discover two secondary metabolites with unusual C-N linkage, respectively. Applied across various microorganisms, HEPE enables record-high clavulanic acid and microcin J25 production, and markedly increases lovastatin yields. With its ability to induce SVs with minimal cytotoxicity, HEPE represents a powerful tool for cryptic metabolite discovery and industrial strain development.</p>

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Enhancing microbial metabolic capacity through high-energy electron beam-induced intense structural variations

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月19日

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  • Xinyuan Feng,
  • Zilong Li,
  • Yifei Zhang,
  • Jingping Xu,
  • Zhenguo Xin,
  • Jinling Yang,
  • Mengjun Wu,
  • Sufen Zhang,
  • Zhiyang Yu,
  • Dongjing Qu,
  • Tao He,
  • Jinmei Wu,
  • Juping Yu,
  • Wei Liu,
  • Mohammad R. Seyedsayamdost,
  • Weishan Wang,
  • Fei Xu

摘要

Small-molecule metabolites are key pharmaceutical resources embedded in complex organismal metabolomes. Scalable microbial production depends on metabolic activation capacity, which in turn requires efficient genetic variation. Structural variants (SVs), key drivers of phenotypic diversity, are pivotal for organism evolution, yet their highly efficient induction remains challenging. While DNA double-strand breaks (DSBs) facilitate SVs formation, existing mutagenesis technologies struggle to balance high DSB efficiency with cellular preservation, particularly in microbial strain improvement for metabolite production. Conventional irradiation methods suffer from low SVs induction rates, making strain enhancement a lengthy and labor-intensive process. Here, we systematically compare six irradiation technologies in Streptomyces lividans 1326 and identify high-energy pulsed electron beams (HEPE) as an approach which effectively induces strong DSBs while preserving cellular integrity. This results in extensive SVs that reshape genome sequences and 3D chromatin structure, leading to activation of secondary metabolite production. By integrating HEPE with high-throughput metabolomics (HEPE-HiTMS), we discover two secondary metabolites with unusual C-N linkage, respectively. Applied across various microorganisms, HEPE enables record-high clavulanic acid and microcin J25 production, and markedly increases lovastatin yields. With its ability to induce SVs with minimal cytotoxicity, HEPE represents a powerful tool for cryptic metabolite discovery and industrial strain development.