Tuberculosis Therapeutics and Drug Resistance: Mechanisms, Challenges, and Emerging Solutions

Abstract

Tuberculosis remains a leading cause of infectious disease mortality worldwide. The effectiveness of tuberculosis control programs is increasingly undermined by the emergence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. A clear understanding of anti-tuberculosis drugs, their molecular targets, and resistance mechanisms is essential for guiding treatment strategies and drug development. This review summarizes current tuberculosis treatment regimens and provides a comprehensive overview of first-line, second-line, and newer anti-tuberculosis drugs, with emphasis on their mechanisms of action and genetic determinants of resistance. Relevant peer-reviewed literature, World Health Organization reports, and experimental studies were reviewed to synthesize current knowledge on tuberculosis therapeutics and resistance mechanisms. First-line drugs primarily target cell wall synthesis, transcription, and protein synthesis, while second-line and newer agents expand activity to energy metabolism and dormant bacilli. Drug resistance arises through target gene mutations, enzymatic drug modification, altered drug activation, efflux mechanisms, and intrinsic cell wall barriers. Resistance to newer drugs such as bedaquiline and delamanid is increasingly reported, often involving alternative genetic pathways beyond classical targets. Sustained effectiveness of tuberculosis treatment requires integration of molecular diagnostics, rational drug use, and continued surveillance of resistance patterns. Advances in newer therapeutics offer promise, but careful stewardship is essential to prevent rapid resistance emergence.

Keywords: Drug Resistance, Mechanisms of Actions, Mycobacterium tuberculosis, Newer Drugs, Tuberculosis Therapeutics