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<p>Colibactin, a metabolite produced by gut bacteria carrying the polyketide synthase (<i>pks</i>) island, is associated with host genotoxicity and tumorigenesis. However, no Food and Drug Administration-approved therapeutics directly target colibactin. Here we show that expression of the intracellular colibactin self-resistance protein (ClbS) on the surface of engineered bacteria shields the host from genotoxic effects across multiple <i>pks</i><sup>+</sup> isolates. The surface display, due to the fusion of ClbS with outer membrane protein A (ClbS–OmpA) in <i>Escherichia coli</i>, effectively reduced colibactin-induced DNA damage and cell cycle arrest in human cell lines and organoids, outperforming <span>D</span>-serine, a small-molecule inhibitor of colibactin synthesis. The engineered strains mitigated intestinal damage in a mouse model of colitis and suppressed tumorigenesis in mouse models of colon cancer caused by <i>pks</i><sup>+</sup> <i>E. coli</i>. Our results show the feasibility of inhibiting bacterial genotoxins in the gut, establishing a starting point for therapeutics targeting other potential cancer-causing bacterial metabolites.</p>

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Surface expression of antitoxin on engineered bacteria neutralizes genotoxic colibactin in the gut

  • 期刊论文

  • 发表日期：

    2025年12月8日

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  • Shaobo Yang,
  • Zongqi Wang,
  • Chengyuan Fang,
  • Mengdi Yang,
  • Saleh Khawaled,
  • Shanna Bonanno,
  • Neel S. Joshi,
  • Yun Wei,
  • Ke Zhang,
  • Valeria Márquez-Pellegrin,
  • Ming Guan,
  • Songqi Zhang,
  • Anna Clara Bader,
  • Ningyuan Ye,
  • Amber E. Haley,
  • Michael K. Dame,
  • Jason R. Spence,
  • Xuesong He,
  • James G. Fox,
  • Ömer H. Yilmaz,
  • Yatrik M. Shah,
  • Rizwan Romee,
  • Jiahe Li

摘要

Colibactin, a metabolite produced by gut bacteria carrying the polyketide synthase (pks) island, is associated with host genotoxicity and tumorigenesis. However, no Food and Drug Administration-approved therapeutics directly target colibactin. Here we show that expression of the intracellular colibactin self-resistance protein (ClbS) on the surface of engineered bacteria shields the host from genotoxic effects across multiple pks+ isolates. The surface display, due to the fusion of ClbS with outer membrane protein A (ClbS–OmpA) in Escherichia coli, effectively reduced colibactin-induced DNA damage and cell cycle arrest in human cell lines and organoids, outperforming D-serine, a small-molecule inhibitor of colibactin synthesis. The engineered strains mitigated intestinal damage in a mouse model of colitis and suppressed tumorigenesis in mouse models of colon cancer caused by pks+ E. coli. Our results show the feasibility of inhibiting bacterial genotoxins in the gut, establishing a starting point for therapeutics targeting other potential cancer-causing bacterial metabolites.