Host–Pathogen Interaction Mapping in Drug-Resistant Tuberculosis: A Systems Biology Framework for Dual Therapeutic Targeting

Multidrug-resistant tuberculosis (MDR-TB) remains a major global threat, with more than 400,000 new cases annually and limited effective therapeutic options. Conventional regimens are prolonged, toxic, and increasingly undermined by emerging resistance. Dual therapeutic strategies combining host-directed therapies (HDTs) and pathogen directed therapies (PDTs) may enhance the treatment efficacy and mitigate resistance evolution. In this study, we constructed a high-confidence Mycobacterium tuberculosis – Homo sapiens protein-protein interactions to identify hub proteins and enriched biological pathways. Key host hubs included TLR2, IL8, and CXCL10, which were enriched in immune response pathways, while major pathogen hubs such as PknG, DprE1, and InhA were linked to cell wall biosynthesis and immune evasion. Molecular docking revealed high-affinity binding for AX20017 with PknG (ΔG = − 9.6 kcal/mol), bedaquiline with ATP synthase (ΔG = − 11.2 kcal/mol), and preomanid with a mycolic acid synthesis enzyme (ΔG = − 8.7 kcal/mol), with binding stability confirmed through molecular dynamics simulations. This systems-level approach highlights the potential of a dual HDT-PDT framework to simultaneously disrupt bacterial persistence and restore host immunity, providing a strong basis for the development of next-generation MDR-TB treatment regimens.