Advancing Therapies for Mycobacterial Diseases: From Small Molecules to Host‐Directed Strategies

The global burden of multidrug-resistant tuberculosis (MDR-TB) and the rising incidence of nontuberculous mycobacterial (NTM) infections highlight the urgent need for innovative therapeutic strategies. Current treatments are prolonged, toxic, and increasingly compromised by resistance and limited diagnostic capacity. This review focuses on emerging therapeutic strategies against Mycobacterium tuberculosis (Mtb) and highlights evidence relevant to NTM whenever available. Specifically, it explores direct anti-mycobacterial small molecules, including the optimization of drug classes, such as hydrazide-hydrazones, isoniazid derivatives, nitrofurans, multicomponent forms, and metal complexes, as well as emerging chemical entities in early-stage development. These compounds target essential bacterial enzymes such as decaprenylphosphoryl-β-d-ribose oxidase (DprE1), enoyl acyl carrier protein reductase (InhA), and deoxyribonucleic acid (DNA) gyrase inhibitors, offering promising avenues for overcoming resistance. The review also examines natural products and phytochemicals, including siderophore inhibitors, plant-derived compounds, and essential oils. Non-classical strategies such as antimicrobial peptides (AMPs) and phage therapy are also discussed. Finally, we discuss the expanding field of host-directed therapies (HDTs), which aim to modulate the host immune response to enhance mycobacterial clearance and reduce tissue damage. Ultimately, advancing mycobacterial treatment will require integrated, mechanism-based regimens that combine new compounds with HDTs and improved delivery systems. Although therapeutic innovation for NTM has lagged, adapting promising TB-focused compounds and implementing NTM-specific screening and validation frameworks are essential. Collaborative efforts across academia, industry, and the public health sector will be key to translating these advances into shorter, safer, and more effective therapies that address the complexity of mycobacterial disease and the rise of antimicrobial resistance.