A Monovalent SMAC Mimetic as a Potential Host-Directed Therapy for Tuberculosis

BACKGROUND: Tuberculosis (TB) caused by the Mycobacterium tuberculosis complex (MTBC) is the leading cause of death from a single infectious agent worldwide. Current antibiotics fail against drug-resistant strains, highlighting the urgent need for novel therapies. Host-directed therapy (HDT), which enhances host immunity rather than targeting pathogens directly, offers a promising solution. METHODS: We use the in vitro cells infection assays and in vivo mouse infection model to identify the effects of a monovalent second mitochondria-derived activator of caspase (SMAC) mimetic named BI82 against mycobacterial infections. RESULTS: We demonstrate that BI82 potently inhibits Mycobacterium bovis growth in macrophages, while exhibiting synergy with rifampicin. BI82 also significantly restricts M. tuberculosis growth in ex vivo whole-blood assays from both tuberculosis patients and healthy donors. BI82 degrades cellular inhibitor of apoptosis protein 1 (cIAP1), promoting infected cell apoptosis as evidenced by elevated cleaved caspase-3 and phosphorylated mixed lineage kinase domain-like levels. In a mouse model, oral BI82 treatment can reduce M. bovis burden in lungs and spleens, alleviate lung lesions, and increase CD3⁺ T cells with elevated CD4/CD8 ratios. CONCLUSIONS: Our findings reveal that BI82 employs a unique apoptosis-dependent mechanism to exert broad-spectrum activity against mycobacterial infections, positioning it as a promising HDT candidate.