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N-ACETYL-CYSTEINE EXHIBITS POTENT ANTI-MYCOBACTERIAL ACTIVITY IN ADDITION TO ITS KNOWN ANTI-OXIDATIVE FUNCTIONS
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Resumo em Inglês
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.
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