Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development. Academic Article uri icon

Overview

abstract

  • The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb's respiratory chain, and highlight the challenges associated with targeting the pathogen's respiratory enzymes for tuberculosis drug development.

publication date

  • October 31, 2019

Research

keywords

  • Antitubercular Agents
  • Drug Development
  • Electron Transport Complex III
  • Electron Transport Complex IV
  • Mycobacterium tuberculosis
  • NADH Dehydrogenase
  • Tuberculosis

Identity

PubMed Central ID

  • PMC6823465

Scopus Document Identifier

  • 85074291754

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-17-0337

PubMed ID

  • 31672993

Additional Document Info

volume

  • 10

issue

  • 1