Development of a covalent inhibitor of gut bacterial bile salt hydrolases
Development of a covalent inhibitor of gut bacterial bile salt hydrolases
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DOI：
10.1038/s41589-020-0467-3
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发表时间：
2020-02-10
影响因子：
14.8
通讯作者：
Devlin, A. Sloan
中科院分区：
文献类型：
--
作者：
Adhikari, Arijit A.;Seegar, Tom C. M.;Devlin, A. Sloan
胆盐水解酶（BSH）广泛地由人类肠道细菌表达并且催化导致次级胆汁酸形成的网关反应。胆汁酸通过与宿主受体结合来调节关键的代谢和免疫过程。对于抑制所有肠道细菌中的BSH以研究胆汁酸对宿主生理学的影响的有效工具存在未满足的需求。在这里，我们报告了肠道细菌BSH的共价泛抑制剂的发展。从一个合理设计的候选库，我们确定了一个铅化合物轴承的α-氟甲基酮弹头，修改BSH在催化半胱氨酸残基。该抑制剂消除了常规小鼠粪便中的BSH活性。单次灌胃该化合物的小鼠显示BSH活性降低，粪便中去结合胆汁酸水平降低。我们的研究表明，BSH共价抑制剂具有调节胆汁酸组成的潜力，而鹅去氧胆酸修饰的细菌胆汁盐水解酶共价泛抑制剂不具有杀菌作用，因此可用于研究胆汁酸对宿主生理的影响。
Bile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and immune processes by binding to host receptors. There is an unmet need for a potent tool to inhibit BSHs across all gut bacteria to study the effects of bile acids on host physiology. Here, we report the development of a covalent pan-inhibitor of gut bacterial BSHs. From a rationally designed candidate library, we identified a lead compound bearing an alpha-fluoromethyl ketone warhead that modifies BSH at the catalytic cysteine residue. This inhibitor abolished BSH activity in conventional mouse feces. Mice gavaged with a single dose of this compound displayed decreased BSH activity and decreased deconjugated bile acid levels in feces. Our studies demonstrate the potential of a covalent BSH inhibitor to modulate bile acid composition in vivo.A covalent pan-inhibitor of bacterial bile salt hydrolases developed by adding a chenodeoxycholic acid moiety to the warhead is not bactericidal and is therefore useful for studying the effects of bile acids on host physiology.