Molecular Mechanisms Underlying Antimicrobial Resistance in Mycobacteria

Antimicrobial resistance in mycobacteria arises from a complex interplay of intrinsic and acquired mechanisms that collectively limit the efficacy of current therapeutic options. Intrinsic resistance is largely driven by the low permeability of the mycobacterial cell envelope, the activity of efflux pumps, and the presence of drug-modifying enzymes, which together restrict intracellular drug accumulation and contribute to broad baseline tolerance. This review integrates resistance mechanisms of both M. tuberculosis and M. abscessus, two clinically relevant mycobacteria that share core molecular pathways while exhibiting species-specific determinants that complicate treatment. Additional intrinsic factors, including biofilm formation and stress-induced adaptive responses, further enhance persistence and reduce susceptibility to multiple drug classes. Acquired resistance predominantly results from chromosomal mutations affecting drug targets or prodrug activation pathways, such as katG, inhA, rpoB, gyrA, and pncA in Mycobacterium tuberculosis, leading to high rates of multidrug-resistant and extensively drug-resistant disease. In nontuberculous mycobacteria, species-specific determinants—including inducible macrolide resistance mediated by erm(41) in M. abscessus, plasmid-mediated erm (55) variants, rrl and rrs mutations, diverse enzymatic inactivation systems, and regulatory alterations in the MarR family that result in inducible resistance to drugs such as ethionamide —generate highly variable resistance profiles that complicate treatment. Recent advances in molecular diagnostics, including PCR-based assays, whole-genome sequencing, CRISPR-based diagnostic platforms, AI-assisted diagnostics, and emerging multi-omics approaches, have improved the detection of resistance-associated mutations and enhanced understanding of mycobacterial pathophysiology. In parallel, new therapeutic agents and optimized regimens offer promising avenues to overcome resistance, although emerging resistance to novel drugs underscores the need for continued surveillance. This review synthesizes current knowledge on the molecular basis of resistance in M. tuberculosis and NTM, highlighting implications for diagnosis, treatment, and future research.