ZFIN ID: ZDB-PUB-190318-2
The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets
Black, H.D., Xu, W., Hortle, E., Roberston, S.I., Britton, W.J., Kaur, A., New, E.J., Witting, P.K., Chami, B., Oehlers, S.H.
Date: 2019
Source: Free radical biology & medicine   135: 157-166 (Journal)
Registered Authors: Hortle, Elinor, Oehlers, Stefan
Keywords: Antioxidant, Cell death, Host-directed therapy, Hypoxia, Infection, Mitochondria, Zebrafish
MeSH Terms:
  • Animals
  • Antioxidants/pharmacology*
  • Bacterial Proteins/genetics*
  • Cyclic N-Oxides/pharmacology*
  • Disease Models, Animal
  • Humans
  • Macrophages/drug effects
  • Macrophages/microbiology
  • Mycobacterium marinum/drug effects
  • Mycobacterium marinum/pathogenicity
  • Mycobacterium tuberculosis/drug effects
  • Mycobacterium tuberculosis/pathogenicity
  • Reactive Oxygen Species/metabolism
  • Tuberculosis/drug therapy*
  • Tuberculosis/genetics
  • Tuberculosis/microbiology
  • Tuberculosis/pathology
  • Zebrafish/genetics
  • Zebrafish/microbiology
PubMed: 30878645 Full text @ Free Radic. Biol. Med.
ABSTRACT
Tuberculosis is a chronic inflammatory disease caused by persistent infection with Mycobacterium tuberculosis. The rise of antibiotic resistant strains necessitates the design of novel treatments. Recent evidence shows that not only is M. tuberculosis highly resistant to oxidative killing, it also co-opts host oxidant production to induce phagocyte death facilitating bacterial dissemination. We have targeted this redox environment with the cyclic nitroxide derivative 4-methoxy-TEMPO (MetT) in the zebrafish-M. marinum infection model. MetT inhibited the production of mitochondrial ROS and decreased infection-induced cell death to aid containment of infection. We identify a second mechanism of action whereby stress conditions, including hypoxia, found in the infection microenvironment appear to sensitise M. marinum to killing by MetT both in vitro and in vivo. Together, our study demonstrates MetT inhibited the growth and dissemination of M. marinum through host and bacterial targets.
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