Published Paper Details:

Tuberculosis continues to represent a major global public health concern, particularly due to the increasing prevalence of drug-resistant strains of Mycobacterium tuberculosis. Despite the availability of effective chemotherapy, the emergence of resistance to both first-line and second-line anti-tuberculosis drugs has significantly undermined disease control efforts worldwide. Unlike many other bacterial pathogens, M. tuberculosis primarily acquires antibiotic resistance through spontaneous chromosomal mutations rather than horizontal gene transfer. These mutations affect drug targets, drug-activating enzymes, transcriptional regulators, and metabolic pathways, leading to reduced drug susceptibility and treatment failure. This review comprehensively examines the molecular mechanisms underlying antibiotic resistance in M. tuberculosis. Resistance to first-line drugs such as isoniazid and rifampicin is largely attributed to mutations in genes including katG, inhA, and rpoB, which impair drug activation or alter target binding. Resistance to second-line agents, including fluoroquinolones and injectable aminoglycosides, is associated with mutations in gyrA, gyrB, and ribosomal components, as well as enzymatic drug modification. In addition, the role of efflux pump systems in mediating multidrug tolerance and contributing to unexplained resistance phenotypes is discussed. These pumps enhance bacterial survival by reducing intracellular drug concentrations and promoting phenotypic heterogeneity.The review also outlines the classification of drug-resistant tuberculosis, including mono-drug resistant, multidrug-resistant, pre-extensively drug-resistant, extensively drug-resistant, and totally drug-resistant tuberculosis, highlighting their clinical and epidemiological significance. Furthermore, emerging evidence on metabolic adaptations, persister cell formation, and stress response pathways that facilitate drug tolerance is addressed. A detailed understanding of these resistance mechanisms is essential for improving molecular diagnostics, optimizing treatment regimens, and guiding the development of novel therapeutic strategies aimed at curbing the global burden of drug-resistant tuberculosis.