Arginine-deprivation-induced oxidative damage sterilizes Mycobacterium tuberculosis

Sangeeta Tiwari, Andries J. Van Tonder, Catherine Vilchèze, Vitor Mendes, Sherine E. Thomas, Adel Malek, Bing Chen, Mei Chen, John Kim, Tom L. Blundell, Julian Parkhill, Brian Weinrick, Michael Berney, William R. Jacobs

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective of their primary macromolecular targets. Inhibitors of targets involved in both combating oxidative stress as well as being required for in vivo survival may exhibit powerful synergistic action. This study demonstrates that the de novo arginine biosynthetic pathway in Mycobacterium tuberculosis (Mtb) is up-regulated in the early response to the oxidative stress-elevating agent isoniazid or vitamin C. Arginine deprivation rapidly sterilizes the Mtb de novo arginine biosynthesis pathway mutants δargB and δargF without the emergence of suppressor mutants in vitro as well as in vivo. Transcriptomic and flow cytometry studies of arginine-deprived Mtb have indicated accumulation of ROS and extensive DNA damage. Metabolomics studies following arginine deprivation have revealed that these cells experienced depletion of antioxidant thiols and accumulation of the upstream metabolite substrate of ArgB or ArgF enzymes. δargB and δargF were unable to scavenge host arginine and were quickly cleared from both immunocompetent and immunocompromised mice. In summary, our investigation revealed in vivo essentiality of the de novo arginine biosynthesis pathway for Mtb and a promising drug target space for combating tuberculosis.

Original languageEnglish (US)
Pages (from-to)9779-9784
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number39
DOIs
StatePublished - 2018

Keywords

  • Bactericidal auxotrophy
  • L-arginine
  • Mycobacterium tuberculosis
  • Oxidative damage
  • Reactive oxygen species

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Arginine-deprivation-induced oxidative damage sterilizes Mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this