Molecular Determinants of Resistance to First-and Second-Line Anti-tuberculosis Drugs: Current Evidence and Future Directions

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious cause of death globally. The rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains has severely complicated disease control. Unlike many bacteria, Mtb develops resistance exclusively through chromosomal mutations that disrupt drug targets, impair prodrug activation, or alter metabolic and regulatory pathways. This review synthesizes and critically evaluates the current evidence on the molecular basis of resistance to first and second-line anti-TB drugs: isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, fluoroquinolones, aminoglycosides, linezolid, bedaquiline, delamanid, pretomanid, ethionamide, and prothionamide. Key resistance-associated genes were examined: katG, inhA, rpoB, embCAB, pncA, rrs, gyrA/B, atpE, Rv0678, and ddn, and explore how epistatic and compensatory interactions between mutations affect bacterial fitness and shape resistance evolution. Progress in whole- genome sequencing, novel drug targets, and precision TB therapy are also discussed. A clearer understanding of these mechanisms is essential for improving diagnostics, designing smarter regimens, and addressing drug- resistant TB, especially in high-burden settings.