The anaerobic conversion of choline to trimethylamine (TMA) by the human gut
microbiota has been linked to multiple human diseases. The potential impact of
this microbial metabolic activity on host health has inspired multiple efforts
to identify small molecule inhibitors. Here, we use information about the
structure and mechanism of the bacterial enzyme choline TMA-lyase (CutC) to
develop a cyclic choline analog that inhibits the conversion of choline to TMA
in bacterial whole cells and in a complex gut microbial community. In
vitro biochemical assays and a crystal structure suggest that this analog is
a competitive, mechanism-based inhibitor. This work demonstrates the utility of
structure-based design to access inhibitors of radical enzymes from the human
gut microbiota.
