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

A strategy to design covalent inhibitors targeting the active site thiyl radical of TMA Lyase under anaerobic conditions led to the discovery of compound 7.

• TMA Lyase is an enzyme expressed in human gut bacteria involved in the formation of trimethylamine oxide (TMAO).
• The catalytic cycle of TMA Lyase involves an active site thiyl radical, which was targeted for covalent inhibition.
• The strategy specifically required anaerobic conditions to engage the catalytic mechanism.
• Compound 7 was described as a 'previously unreported highly potent and selective inhibitor of TMA Lyase.'

Compound 7 was identified as a highly potent and selective small-molecule inhibitor of TMA Lyase.

• Compound 7 acts as a covalent inhibitor targeting the active site thiyl radical of TMA Lyase.
• The compound demonstrated high potency and selectivity as described in the study title and abstract.
• The discovery resulted from a rational design strategy focused on the anaerobic catalytic mechanism of TMA Lyase.

Oral dosing of compound 7 in rats produced a significant reduction of circulating TMAO levels.

• Compound 7 was administered orally to rats.
• A statistically significant reduction in circulating TMAO levels was observed following oral dosing.
• TMAO is a metabolite implicated in the development of heart failure.
• The in vivo efficacy was demonstrated in a rat model system.

Compound 7 demonstrated inhibition of TMAO generated from a human microbiome in a human fecal mouse transplant model.

• A human fecal mouse transplant model was used to assess inhibition of TMAO production from a human microbiome.
• Compound 7 showed inhibitory activity against TMAO production specifically derived from human gut bacteria.
• This model provided translational evidence of efficacy relevant to human gut microbiome-derived TMAO.
• The fecal transplant model was used to specifically profile activity against human microbiome-derived TMA/TMAO production.

TMAO, produced via anaerobic choline metabolism by gut bacteria through TMA Lyase, is implicated in the development of heart failure.

• TMA Lyase is expressed in human gut bacteria and plays a 'pivotal role in the formation of trimethylamine oxide (TMAO).'
• TMAO is described as 'a metabolite implicated in the development of heart failure.'
• Inhibition of TMA Lyase represents a strategy to reduce circulating TMAO levels.
• The metabolic pathway involves anaerobic choline metabolism by human gut bacteria.