Molecular Mechanisms of Resistance and Treatment Efficacy of Delamanid Against <i>Mycobacterium tuberculosis</i>: A Systematic Review

Background and aims Tuberculosis (TB) remains a major global health problem, and treatment progress is increasingly threatened by rising multidrug-resistant tuberculosis (MDR-TB). Delamanid (DLM), a nitroimidazole drug, has shown good efficacy and safety against both drug-susceptible and drug-resistant Mycobacterium tuberculosis ( Mtb ) strains. However, data on its resistance mechanisms, drug susceptibility testing (DST), clinical effectiveness, safety, and pharmacokinetics remain limited. This review aims to summarize the most recent molecular, structural, and clinical evidence related to DLM. Methods A comprehensive literature search was performed using WHO publications and major scientific databases, including PubMed, Web of Science, Embase, Scopus, and the Cochrane Library. Studies published through 2024 and early 2025 on DLM resistance, mechanisms of action, DST, pharmacokinetics, safety, and treatment outcomes were included. Structural analyses of key proteins involved in DLM activation were carried out using crystal structures and AlphaFold models. Results Recent research identified multiple mutations in the F420-dependent activation pathway, particularly in ddn , fgd1 , fbiA , fbiB , fbiC , and fbiD that contribute to DLM resistance. Structural modeling demonstrated how these mutations affect protein stability and cofactor binding. Clinical studies showed that DLM-containing regimens improve culture conversion and treatment success, especially when combined with oral agents such as bedaquiline and linezolid. Safety data indicate that DLM is generally well tolerated, with QT prolongation being the main but manageable adverse effect. Conclusion DLM is an important and effective component of MDR-/XDR-TB treatment. A clearer understanding of its resistance mechanisms, pharmacological properties, and clinical outcomes can support better regimen design and help prevent the development of further resistance.