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.