N-Acetylcysteine as a Host-Directed Therapy Against Clarithromycin-Resistant .

(1) Background: The treatment of () infections resistant to clarithromycin (CLR) is highly challenging. Traditional non-tuberculous mycobacteria (NTM) chemotherapy may disturb the immune homeostasis of the host by increasing oxidative stress; therefore, host-directed immunotherapy is an alternative option for infections caused by . (2) Method: A clinical isolate of CLR-resistant was screened, and then the therapeutic effects of N-acetylcysteine (NAC) against CLR-resistant infection were evaluated in Tohoku Hospital Pediatrics-1 (THP-1) cells and murine models. RNA sequencing and Western blot were used to profile the protective immune responses induced by NAC. The contribution of candidate signaling pathways was confirmed by the corresponding inhibitor and agonist. (3) Results: NAC immunotherapy led to a significant reduction in bacterial loads both in THP-1 cells and murine infection models, which was associated with enhanced antioxidant effects and downregulation of apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein ki-nase/extracellular signal-regulated kinase 3/6 (MKK3/6)-p38 mitogen-activated protein kinase (MAPK)-mediated inflammatory immune responses. The inhibitor of p38 signaling mimicked the protective effect of NAC, while the agonist attenuated it, suggesting that the p38 pathway is crucial in NAC-mediated immune protection against infection. (4) Conclusion: Our study suggests that NAC could be used as a host-directed therapy agent against drug-resistant infection.