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

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.