Engineered romidepsin biosynthetic pathways in Escherichia coli Nissle 1917 improve the efficacy of bacteria-mediated cancer therapy

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Abstract
The probiotic strain Escherichia coli Nissle 1917 (EcN), a potential member of tumor-targeting bacteria, shows great promise for cancer treatment. By leveraging engineered EcN, we can design a bacteria-assisted, tumor-targeted therapy for the biosynthesis and targeted delivery of small-molecule anticancer agents. In this study, we aimed to use EcN as a base for synthesizing Romidepsin (FK228), an FDA-approved drug originally made by Chromobacterium violaceum No. 96. Through gene cluster reconstruction, promoter optimization, and genome modification, we created FK228-producing strains to boost anticancer efficacy. The engineered strain achieved a maximum in vitro yield of 1.5 mg/L. In 4T1 tumor-bearing BALB/c mouse xenograft models, six recombinant strains outperformed the wild-type EcN. Proteome showed that inflammatory response induced by EcN combined with intratumoral FK228 production improved treatment results. Also, targeted synthesis reduced FK228's cardiotoxicity and mortality. Engineered EcN enables drug biosynthesis and precise delivery, offering powerful anticancer activity.
Funding Information
  • National Natural Science Foundation of China (32201245)
  • National Natural Science Foundation of China (32122049)
  • National Natural Science Foundation of China (32161133013)
  • Fundamental Research Funds of Shandong University (2023QNTD001)
  • Future Plan for Young Sholars of Shandong University
  • Fund for Distinguished Young Scholars of SDU
  • Natural Science Foundation of Shandong Province (ZR2022JQ11)
  • SKLMT Frontiers and Challenges Project (SKLMTFCP-2023-05)
  • Shenzhen Science and Technology Program (ZDSYS20220303153551001)
  • 111 Project (B16030)
  • the Intestinal Microbiology Research Fund of the Institute of Microbiology Technology (cdwswjj-2025-02)

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