Therapeutic Strategies for Tuberculosis: Progress and Lessons Learned.

Tuberculosis (TB) remains a significant global health challenge, ranking second only to COVID-19 as the leading cause of death from a single infectious agent, with 1.3 million TB-related deaths reported in 2022. Treatment efficacy has been compromised by the emergence of drug-resistant strains, including rifampin-resistant TB (RR-TB), multidrug-resistant TB (MDR-TB), and extensively drug-resistant TB (XDR-TB). Although first-line drugs like isoniazid, rifampicin, pyrazinamide, and ethambutol form the cornerstone of TB therapy, the rise of resistant strains necessitates the use of second-line drugs, which often come with increased toxicity and limited accessibility. Recent advances have focused on repurposing existing compounds and developing new drugs with novel mechanisms of action. Promising agents such as second-generation bedaquiline analogs (TBAJ-587, TBAJ-876), sudapyridine (WX-081), delamanid, pretomanid, and TBI-166 (pyrifazimine) have shown efficacy against resistant Mtb strains. Innovative treatment regimens like the BPaLM protocol-combining bedaquiline, pretomanid, linezolid, and moxifloxacin-offer shorter, all-oral therapies with higher cure rates. Personalized treatment durations and dose optimizations are becoming feasible through risk stratification algorithms and pharmacokinetic/pharmacodynamic studies. Immunotherapy is emerging as a complementary strategy to enhance the host's immune response against Mtb. Agents such as vitamin D, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), statins, metformin, and biological agents like interleukins and granulocyte-macrophage colony-stimulating factor are under exploration. Additionally, cell therapies involving mesenchymal stem cells and immune effector cells present new therapeutic avenues. Despite these advancements, significant challenges remain in achieving the World Health Organization's "End TB Strategy" goals, particularly as the COVID-19 pandemic has diverted resources and attention. Ongoing research and global collaboration are crucial to develop novel therapeutic strategies, optimize treatment regimens, and ultimately reduce the global burden of TB.