N-Acetylcysteine as a Host-Directed Therapy Against Clarithromycin-Resistant Mycobacterium abscessus

Area of Science:

• Immunology
• Microbiology
• Pharmacology

Background:

• Clarithromycin-resistant Mycobacterium abscessus infections present significant treatment challenges.
• Conventional therapies for non-tuberculous mycobacteria can disrupt host immune homeostasis.
• Host-directed immunotherapy offers a potential alternative for M. abscessus infections.

Purpose of the Study:

• To evaluate the therapeutic efficacy of N-acetylcysteine (NAC) against clarithromycin-resistant M. abscessus.
• To investigate the underlying immune mechanisms of NAC's protective effects.
• To explore NAC as a host-directed therapy for drug-resistant M. abscessus.

Main Methods:

• Screening of a clarithromycin-resistant M. abscessus clinical isolate.
• In vitro (THP-1 cells) and in vivo (murine models) evaluation of NAC's therapeutic effects.
• RNA sequencing and Western blot to analyze immune responses; pathway analysis using inhibitors and agonists.

Main Results:

• NAC immunotherapy significantly reduced bacterial loads in both cellular and murine models.
• NAC treatment enhanced antioxidant effects and downregulated ASK1-MKK3/6-p38 MAPK inflammatory pathways.
• p38 MAPK pathway inhibition mimicked NAC's protective effects, while agonism attenuated them, confirming pathway's crucial role.

Conclusions:

• N-acetylcysteine demonstrates significant therapeutic potential against drug-resistant Mycobacterium abscessus.
• NAC functions as a host-directed therapy by modulating oxidative stress and specific inflammatory signaling pathways.
• NAC represents a promising agent for combating challenging clarithromycin-resistant M. abscessus infections.