<i>Philadelphus tenuifolius</i> Leaf Extract Exhibits Anti-Tuberculosis Activity by Enhancing Host Autophagy and Immunity: A Promising Host-Directed Therapeutic Candidate

The global emergence of drug-resistant <i>Mycobacterium tuberculosis</i> (Mtb) necessitates the urgent discovery of novel anti-tuberculosis agents. <i>Philadelphus tenuifolius</i> Rupr., a Korean aromatic herb, has been historically recognized for its traditional medicinal uses. This study aimed to scientifically investigate the anti-tuberculosis (TB) potential of the <i>P. tenuifolius</i> leaf extract (PT-LE) and elucidate its underlying mechanism of action. PT-LE was prepared by 50% ethanolic extraction. Its anti-TB activity was evaluated against intracellular Mtb in BMDMs. Mechanistic studies focused on the activation of the MAPK pathway and autophagy flux. Synergistic effects with conventional anti-TB drugs were also assessed. For the <i>in vivo</i> evaluation, Mtb-infected mice were orally treated daily with PT-LE (100 mg/kg), followed by the determination of the lung bacterial burden. PT-LE exhibits negligible host cell cytotoxicity and effectively reduced the bacterial load of intracellular Mtb within macrophages. Mechanistically, PT-LE was shown to significantly activate the MAPK signaling pathway, which subsequently enhanced autophagy flux - a critical host defense mechanism against Mtb. Furthermore, PT-LE demonstrated potent synergistic activity with existing anti-TB drugs and modulated the host immune response by increasing the production of the chemokine MCP-1. Critically, the <i>in vivo</i> experiments showed that oral administration of PT-LE significantly reduced the Mtb bacterial burden in the lungs of infected mice. These findings reveal a novel anti-TB function of PT-LE, which operates by enhancing host autophagy and immunity. PT-LE represents a promising and effective host-directed therapeutic candidate for both drug-sensitive and drug-resistant tuberculosis.