N-acetyl-cysteine Exhibits Potent Anti-Mycobacterial Activity in Addition to Its Known Anti-Oxidative Functions

BMC Microbiol. 2016 Oct 28;16(1):251. doi: 10.1186/s12866-016-0872-7.

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.

Methods: Oxidative 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.

Results: PTB 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.

Conclusions: NAC 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.

Keywords: Antimicrobial activity; N-acetyl cysteine; Therapy; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylcysteine / pharmacology*
  • Adolescent
  • Adult
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Antioxidants / pharmacology*
  • Case-Control Studies
  • Cell Death / drug effects
  • Cell Line
  • Disease Models, Animal
  • Humans
  • Latent Tuberculosis / blood
  • Latent Tuberculosis / drug therapy
  • Latent Tuberculosis / microbiology
  • Lipid Peroxidation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Mycobacterium avium / drug effects
  • Mycobacterium avium / growth & development
  • Mycobacterium avium / metabolism
  • Mycobacterium bovis / drug effects
  • Mycobacterium bovis / growth & development
  • Mycobacterium bovis / metabolism
  • Mycobacterium tuberculosis / drug effects*
  • NADPH Oxidases / deficiency
  • NADPH Oxidases / metabolism
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism
  • Tuberculosis, Pulmonary / blood
  • Tuberculosis, Pulmonary / drug therapy
  • Tuberculosis, Pulmonary / microbiology
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Antioxidants
  • Reactive Oxygen Species
  • NADPH Oxidases
  • Acetylcysteine