Discovery of a Highly Potent and Selective Small-Molecule Inhibitor of In Vivo Anaerobic Choline Metabolism by Human Gut Bacteria

Journal of Medicinal Chemistry 2026

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Authors: Mariell Pettersson, Giuseppina La Sala, Anders Gunnarsson, Anna Vildhede, Ben Sparklin, Björn Holm, Dušan Petrović, Ginger Lasky, Scott Turick, Marta Szydlowska, Vancheswaran Gopalakrishnan, Tina Bake
+14 more Jens Petersen, Jonas Brånalt, Kristina Westerlund, Marcel Taillefer, Marcus Henricsson, Margareta Ek, Paul Warrener, Robert Roth, Taylor S. Cohen, Tove Sjögren, Ulf Fahlander, Ulrik Jurva, Yannick Morias, John Liddle
DOI: 10.1021/acs.jmedchem.5c01451
Cited by: 2
References: 44

Abstract

Trimethylamine (TMA) Lyase is an enzyme expressed in human gut bacteria that plays a pivotal role in the formation of trimethylamine oxide (TMAO), a metabolite implicated in the development of heart failure. Here, we describe a strategy to design covalent inhibitors targeting the active site thiyl radical involved in the catalytic cycle of the enzyme under anaerobic conditions. This strategy led to the discovery of 7, a previously unreported highly potent and selective inhibitor of TMA Lyase. When dosed orally to rats, 7 shows a significant reduction of circulating TMAO levels and, importantly, demonstrates inhibition of TMAO generated from a human microbiome when profiled in a human fecal mouse transplant model.

Fields of Study & Subjects

Gut microbiota and health Metabolism and Genetic Disorders Anaerobic Digestion and Biogas Production

Publication details

Journal / source
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Volume
69
Issue
3
Pages
2115–2129
Publication date
30 January 2026
Language
EN