Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site. Academic Article uri icon

Overview

abstract

  • Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.

publication date

  • January 8, 2021

Research

keywords

  • Antitubercular Agents
  • Bacterial Proteins
  • Carboxy-Lyases
  • Mycobacterium smegmatis
  • Mycobacterium tuberculosis
  • Peptide Synthases

Identity

PubMed Central ID

  • PMC7794376

Scopus Document Identifier

  • 85099005007

Digital Object Identifier (DOI)

  • 10.1007/978-1-4939-2450-9_6

PubMed ID

  • 33420031

Additional Document Info

volume

  • 12

issue

  • 1