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合成胆汁酸的结构导向设计可以抑制Clostridioides difficile TcdB毒素

Sean Miletic¹, Simoun Icho^1,2, Zhijie Li¹

¹Molecular Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.

Nature microbiology

|November 18, 2025

概括

肠道胆酸通过锁定其结构来抑制Clostridioides difficile毒素B,防止细胞损伤. 新型胆汁酸衍生物为C. difficile感染提供了潜在的口服疗法.

科学领域:

微生物学微生物学
结构生物学结构生物学
药物发现药物发现药物发现

背景情况:

Clostridioides 难毒素 B (TcdB) 是一个关键的毒性因子,导致传染性腹和结肠炎.
已知肠道胆酸可以抑制TcdB,但机制尚不清楚.

研究的目的:

阐明胆酸抑制TcdB的结构机制.
开发新的,肠道受限的胆酸衍生物,作为C. difficile感染的潜在治疗方法.

主要方法:

低温电子显微镜 (cryo-EM) 用于确定与抑制胆酸结合的TcdB的结构.
肠道受限胆酸衍生物的结构导向设计和合成.
在C. difficile感染的小鼠模型中对胆汁酸衍生物的体内测试.

主要成果:

低温-EM结构显示,胆酸与TcdB C终端CROP域结合,以异质方式掩盖受体结合部位.
一种合成的肠道受限胆酸衍生物sBA-2在口服后在肠道中被保留.
sBA-2有效地保护小鼠免受C. difficile毒素诱导的疾病病理.

结论:

胆酸通过诱导其CROP域中的构造锁来抑制TcdB,防止宿主细胞相互作用.
肠道受限胆酸衍生物是开发口服治疗C. difficile的有希望的策略.
这项研究为TcdB抑制和治疗开发提供了结构性基础.

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