N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions

Autor(es)

Amaral, Eduardo P. ; Conceicao, Elisabete L. ; Costa, Diego L. ; Rocha, Michael S. ; Marinho, Jamocyr M. ; Cordeiro-Santos, Marcelo ; D'Imperio-Lima, Maria Regina ; Barbosa, Theolis ; Sher, Alan ; Andrade, Bruno B.

• Tipo de documento: Artigo Científico
• Fonte: BMC Microbiology; v. 16, OCT 28 2016.
• Citações Web of Science: 14

Resumo

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. (AU)

• Processo FAPESP: 13/07298-5 - Avaliação do envolvimento de catepsinas lisossomais na ativação do inflamassoma NLRP3 induzida por ESAT-6 recombinante de Mycobacterium tuberculosis
• Beneficiário: Eduardo Pinheiro Amaral
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 10/51150-4 - Modelo animal para análise da patogenicidade de cepas de Mycobacterium bovis e avaliação da resposta imune celular e humoral contra isolados patogênicos
• Beneficiário: Maria Regina D'Império Lima
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/19126-0 - Avaliação do papel do receptor P2X7 na modulação da ativação e morte celular dos macrófagos pulmonares durante a indução de formas agressivas de Tuberculose
• Beneficiário: Eduardo Pinheiro Amaral
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado