Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2020 Feb 12

PMID 32042200

Citations 47

Authors

Arijit A Adhikari

Tom C M Seegar

Scott B Ficarro

Megan D McCurry

Deepti Ramachandran

Lina Yao

Snehal N Chaudhari

Sula Ndousse-Fetter

Alexander S Banks

Jarrod A Marto

Stephen C Blacklow

A Sloan Devlin

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

New insights into microbial bile salt hydrolases: from physiological roles to potential applications.

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