Inhibition of Trimethylamine Production by Targeting Bacterial BbuA-mediated γ-butyrobetaine Metabolism

Trimethylamine (TMA) and its metabolite, trimethylamine-N oxide (TMAO), are chemical compounds of bacterial origin. TMA is produced in the human body by gut microbiota and further metabolized into TMAO by hepatic monooxygenase. High TMAO levels have been associated with several pathological conditions, including trimethylaminuria, atherosclerosis, renal failure, type 2 diabetes, and cancer. Preventing their production has been suggested to have a beneficial influence on health. In this study, we designed and tested substrate analogues of a recently discovered and characterized enzyme BbuA (γ-butyrobetaine-CoA oxidoreductase) and demonstrated that it is possible to suppress the TMA producing activity of BbuA enzyme with such designed inhibitors. Among the 12 compounds tested, two exhibited measurable but weak inhibitory activity, with IC50 values of 55.48 and 46.25 mM, respectively.