TY - JOUR T1 - The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden <em>in vivo</em> through host and bacterial targets JF - bioRxiv DO - 10.1101/464586 SP - 464586 AU - Harrison D Black AU - Wenbo Xu AU - Elinor Hortle AU - Sonia I Roberston AU - Warwick J Britton AU - Amandeep Kaur AU - Elizabeth J New AU - Paul K Witting AU - Belal Chami AU - Stefan H Oehlers Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/11/11/464586.abstract N2 - 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. ER -