The autophagy-targeting compound V46 enhances antimicrobial responses to Mycobacteroides abscessus by activating transcription factor EB

Mycobacteroides abscessus (Mabc) is a rapidly growing nontuberculous mycobacterium that poses a considerable challenge as a multidrug-resistant pathogen causing chronic human infection. Effective therapeutics that enhance protective immune responses to Mabc are urgently needed. This study introduces trans-3,5,4′-trimethoxystilbene (V46), a novel resveratrol analogue with autophagy-activating properties and antimicrobial activity against Mabc infection, including multidrug-resistant strains. Among the resveratrol analogues tested, V46 markedly inhibited the growth of both rough and smooth Mabc strains in murine bone marrow-derived macrophages and in the lungs of infected mice. Additionally, V46 significantly reduced Mabc-induced increases in chemokine and pro inflammatory cytokine levels in macrophages and in vivo during infection. Mechanistic analysis showed that V46 suppressed the activation of the AKT-mammalian target of rapamycin signaling pathway and enhanced AMP-activated protein kinase signaling in Mabc-infected cells. Notably, V46 activated autophagy and nuclear translocation of transcription factor EB, which is crucial for antimicrobial host defenses against Mabc. Furthermore, V46 upregulated genes associated with autophagy and lysosomal biogenesis in Mabc-infected bone marrow-derived macrophages. The combination of V46 and rifabutin exerted a synergistic antimicrobial effect. These findings identify V46 as a candidate host-directed therapeutic for Mabc infection that activates autophagy and lysosomal function via transcription factor EB.