Development of a covalent inhibitor of gut bacterial bile salt hydrolases

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 acros...

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Published inNature chemical biology Vol. 16; no. 3; pp. 318 - 326
Main Authors Adhikari, Arijit A, Seegar, Tom C M, Ficarro, Scott B, McCurry, Megan D, Ramachandran, Deepti, Yao, Lina, Chaudhari, Snehal N, Ndousse-Fetter, Sula, Banks, Alexander S, Marto, Jarrod A, Blacklow, Stephen C, Devlin, A Sloan
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.03.2020
Subjects
Acids
Amidohydrolases - antagonists & inhibitors
Amidohydrolases - metabolism
Amidohydrolases - physiology
Animals
Bacteria
Bacteria - enzymology
Bile
Bile acids
Bile Acids and Salts - metabolism
Chenodeoxycholic acid
Covalence
Drug Design
Feces
Female
Gastrointestinal Microbiome - physiology
Humans
Hydrolase
Inhibitors
Lead compounds
Male
Mice
Mice, Inbred C57BL
Physiology
Receptors
Salts
Small Molecule Libraries
Warheads
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Summary: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.
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A.A.A and A.S.D conceived the project and designed the experiments. A.A.A. performed most of the experiments. T.C.S. and S.C.B. performed the crystallization studies. S.B.F. and J.A.M. performed the mass spectrometry studies. D. R. and A.S.B. performed the in vivo experiments and provided fresh mouse feces. M.D.M. purified and performed experiments with B. longum BSH and performed kinetic studies with B. theta BSH. L.Y. performed the in vitro FXR assays and provided help with experiments. S.N.C. performed the cell culture assays. S.N. assisted with bacterial culture experiments. A.A.A. and A.S.D wrote the manuscript. All authors edited and contributed to the critical review of the manuscript.
Author Contributions
ISSN:1552-4450
1552-4469
DOI:10.1038/s41589-020-0467-3