Discovery of a Cyclic Choline Analog That Inhibits Anaerobic Choline Metabolism by Human Gut Bacteria

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Oct 16

PMID 33062182

Citations 8

Authors

Maud Bollenbach

Manuel Ortega

Marina Orman

Catherine L Drennan

Emily P Balskus

Affiliations

Soon will be listed here.

Abstract

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. 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.

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