Host-Directed Therapeutic for the treatment of Mycobacterium tuberculosis

Abstract

This comprehensive review examines the emerging role of Host-Directed Therapies (HDTs) as complementary approaches to conventional Tuberculosis (TB) treatment. The review focuses on diverse HDT mechanisms utilizing their modulators like small molecule, protein-based, lipid-based, vitamin-based, and polysaccharide-based therapeutics. Key mechanisms include autophagy induction through multiple pathways, including mTOR inhibition, calcium signaling modulation, and TFEB activation. Notable compounds such as dimethyl itaconate, tamoxifen, and berbamine demonstrate significant efficacy in enhancing autophagosome formation and bacterial clearance. Matrix metalloproteinase inhibitors like doxycycline show promise in reducing tissue damage and cavity formation. The review highlights the importance of metabolic modulation through compounds like metformin and ezetimibe, which target cellular energy pathways and cholesterol metabolism respectively. Immunomodulatory approaches, including phosphodiesterase inhibition and cytokine regulation, demonstrate potential in optimizing host immune responses. Novel mechanisms such as ferroptosis inhibition and pyroptosis modulation present promising therapeutic avenues. The review also examines the role of established drugs being repurposed for TB treatment, including statins and antidepressants. While preclinical evidence supports the efficacy of various HDTs, the review emphasizes the need for careful consideration of host-pathogen interactions and potential immunological approaches. The complexity of TB pathophysiology necessitates a personalized approach to HDT implementation. Future research directions should focus on clinical validation, optimal dosing strategies, and combination approaches with standard antimicrobial therapy. This review underscores the potential of HDTs to address drug resistance and persistent infections, while highlighting the importance of continued investigation into their safety and efficacy across diverse patient populations.