Abstract
Background Mycobacterium tuberculosis infection is thought to induce oxidative stress. N-acetyl-cysteine (NAC) is widely used in patients with chronic pulmonary diseases including tuberculosis due to its mucolytic and anti-oxidant activities. Here, we tested whether NAC exerts a direct antibiotic activity against mycobacteria.MethodsOxidative stress status in plasma was compared between pulmonary TB (PTB) patients and those with latent M. tuberculosis infection (LTBI) or healthy uninfected individuals. Lipid peroxidation, DNA oxidation and cell death, as well as accumulation of reactive oxygen species (ROS) were measured in cultures of primary human monocyte-derived macrophages infected with M. tuberculosis and treated or not with NAC. M. tuberculosis, M. avium and M. bovis BCG cultures were also exposed to different doses of NAC with or without medium pH adjustment to control for acidity. The anti-mycobacterial effect of NAC was assessed in M. tuberculosis infected human THP-1 cells and bone marrow-derived macrophages from mice lacking a fully functional NADPH oxidase system. The capacity of NAC to control M. tuberculosis infection was further tested in vivo in a mouse (C57BL/6) model.ResultsPTB patients exhibited elevated levels of oxidation products and a reduction of anti-oxidants compared with LTBI cases or uninfected controls. NAC treatment in M. tuberculosis-infected human macrophages resulted in a decrease of oxidative stress and cell death evoked by mycobacteria. Importantly, we observed a dose-dependent reduction in metabolic activity and in vitro growth of NAC treated M. tuberculosis, M. avium and M. bovis BCG. Furthermore, anti-mycobacterial activity in infected macrophages was shown to be independent of the effects of NAC on the host NADPH oxidase system in vitro. Short-term NAC treatment of M. tuberculosis infected mice in vivo resulted in a significant reduction of mycobacterial loads in the lungs.ConclusionsNAC exhibits potent anti-mycobacterial effects and may limit M. tuberculosis infection and disease both through suppression of the host oxidative response and through direct antimicrobial activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-016-0872-7) contains supplementary material, which is available to authorized users.
Highlights
Mycobacterium tuberculosis infection is thought to induce oxidative stress
NAC inhibits oxidative stress, lipid peroxidation, DNA oxidation and cell death in M. tuberculosis-infected human macrophages Previous studies in active TB patients point to an association of this disease with excessive oxidative stress by demonstrating decreased systemic concentrations of antioxidants and enhanced spontaneous generation of free radicals compared to individuals without TB [27, 39]
Following M. tuberculosis infection in vitro, human monocyte-derived macrophages displayed augmented lipid peroxidation (Fig. 1d), DNA oxidation (Fig. 1e) and cell death induction (Fig. 1f ), which were accompanied by a dramatic accumulation of intracellular reactive oxygen species (ROS) (Fig. 1g)
Summary
N-acetyl-cysteine (NAC) is widely used in patients with chronic pulmonary diseases including tuberculosis due to its mucolytic and anti-oxidant activities. NAC’s mucolytic activity is the basis of its use in liquefying sputum samples for the microscopic detection of acid-fast bacilli (AFB) in suspected pulmonary tuberculosis (TB) patients [5]. In both experimental animal models and clinical studies, NAC displays a protective effect on acute liver injury induced by anti-TB drugs in acetaminophen-dependent or independent conditions [6,7,8,9,10,11]. In patients with type 2 diabetes, NAC holds promise in primary prevention of cardiovascular complications and systemic inflammation [12,13,14]
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