A Gut-Restricted Lithocholic Acid Analog as an Inhibitor of Gut Bacterial Bile Salt Hydrolases

Jul 19, 2021ACS chemical biology

A gut-targeted compound that blocks gut bacteria from breaking down bile salts

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Abstract

A new compound, AAA-10, effectively inhibits bile salt hydrolase (BSH) activity and alters bile acid composition in mice.

AAA-10 is designed with a C3-sulfonated lithocholic acid structure and an alpha-fluoromethyl ketone component, enhancing its potency.
The compound shows reduced off-target effects and lower toxicity in mammalian cells compared to earlier inhibitors.
In experiments, AAA-10 successfully inhibited BSH activity in mouse and human fecal samples, bacterial cultures, and purified BSH proteins.
Oral administration of AAA-10 to wild-type mice for 5 days led to decreased levels of secondary bile acids, specifically deoxycholic acid and lithocholic acid, in the gastrointestinal tract.
Low systemic exposure of AAA-10 suggests it is primarily active within the gut.

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Bile acids play crucial roles in host physiology by acting both as detergents that aid in digestion and as signaling molecules that bind to host receptors. Gut bacterial bile salt hydrolase (BSH) enzymes perform the gateway reaction leading to the conversion of host-produced primary bile acids into bacterially modified secondary bile acids. Small molecule probes that target BSHs will help elucidate the causal roles of these metabolites in host physiology. We previously reported the development of a covalent BSH inhibitor with low gut permeability. Here, we build on our previous findings and describe the development of a second-generation gut-restricted BSH inhibitor with enhanced potency, reduced off-target effects, and durableefficacy. Structure-activity relationship (SAR) studies focused on the bile acid core identified a compound, AAA-10, containing a C3-sulfonated lithocholic acid scaffold and an alpha-fluoromethyl ketone warhead as a potent pan-BSH inhibitor. This compound inhibits BSH activity in mouse and human fecal slurry, bacterial cultures, and purified BSH proteins and displays reduced toxicity against mammalian cells compared to first generation compounds. Oral administration of AAA-10 to wild-type mice for 5 days resulted in a decrease in the abundance of the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) in the mouse GI tract with low systemic exposure of AAA-10, demonstrating that AAA-10 is an effective tool for inhibiting BSH activity and modulating bile acid pool composition. in vivo in vivo

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A Gut-Restricted Lithocholic Acid Analog as an Inhibitor of Gut Bacterial Bile Salt Hydrolases

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