Redox homeostasis as a target for new antimycobacterial agents

Abstract Despite early treatment with anti-mycobacteria combination therapy, drug resistance continues to emerge. Maintenance of redox homeostasis is essential for Mycobacterium Avium (M. avium) survival and growth. The aim of the present study was to investigate the antimycobacterial activity of two pro-glutathione (GSH) drugs, which are able to induce redox stress in M. avium and to modulate cytokine production from macrophages. Hence, we investigated two molecules shown to possess antiviral and immunomodulatory properties: C4-GSH, an N-butanoyl GSH derivative, and I-152, a pro-drug of N-acetyl-cysteine (NAC) and beta-mercaptoethylamine (MEA). Both molecules showed activity against replicating M. avium, both in the cell-free model and inside macrophages. Moreover, they were even more effective in reducing the viability of the bacteria that had been kept in water for seven days, proving to be active against both replicating and non-replicating bacteria. By regulating the macrophage redox state, I-152 modulated cytokine production. In particular, higher levels of IFN-γ, IL-1b, IL-18, and IL-12, which are known to be crucial for the control of intracellular pathogens, were found after I-152 treatment. Our results show that C4-GSH and I-152, by inducing perturbation of redox equilibrium, exert bacteriostatic and bactericidal activity against M. avium. Moreover, I-152 can boost the host reponse by inducing the production of cytokines which serve as key regulators of the Th1 response.