Phenothiazine-Driven Autophagic Response in Macrophages as an Anti-cutaneous Tuberculosis Approach

Abstract Cutaneous tuberculosis (CTB), caused by Mycobacterium tuberculosis (Mtb) infection of the skin, remains a global health burden, underscoring the urgent need for more effective drugs and therapeutic strategies. In this study, we discovered a phenothiazine-based derivative, pyridine-embedded phenothiazinium (PEP), as a promising anti-cutaneous tuberculosis agent with potent efficacy both in vitro and in vivo. Upon light illumination, PEP produces abundant reactive oxygen species (ROS), including type I and type II species, enabling direct mycobacterial killing. Beyond its photodynamic bactericidal activity, PEP also functions as a host-directed therapeutic agent by suppressing mTOR signaling and subsequently inducing autophagy in infected host cells. This dual mechanism synergistically enhances intracellular Mtb clearance, integrating ROS-mediated eradication with autophagy-dependent bacterial elimination. Notably, PEP markedly reduces bacterial burden in a murine CTB model and mitigates infection-associated skin pathology. Collectively, our findings unveil the potential of PEP as a promising dual-action therapeutic approach for the efficient treatment of CTB.