Molecular Epidemiology of Drug-Resistant Mycobacterium tuberculosis: Mutation Profiles and Resistance Associations

Background: The global burden of drug-resistant Mycobacterium tuberculosis continues to threaten tuberculosis control efforts, largely due to the emergence and transmission of resistance-associated genetic mutations. Molecular epidemiology provides critical insights into mutation profiles and resistance associations, yet the interplay among key mutations and their contributions to complex resistance patterns remains poorly understood, particularly in high-burden settings. Methods: A retrospective, cross-sectional, laboratory-based design was used to analyze 111 phenotypically confirmed drug-resistant isolates. Molecular drug susceptibility testing (DST) for first- and second-line anti-tuberculosis drugs was performed at the National Health Laboratory Service (NHLS) TB reference laboratory. Drug-resistance profiles were classified according to World Health Organization (WHO) definitions. Descriptive and inferential statistical analyses were conducted to determine mutation frequencies, co-occurrence patterns, and associations with resistance profiles. Results: rpoB (D435V 38.7%; S450L 36.0%) and katG (S315T 80.2%) mutations predominated, forming the core molecular basis of MDR-TB, while 15% harbored inhA promoter mutations associated with low-level isoniazid resistance. The most frequent combinations included rpoB S450L with katG S315T and rpoB D435V with katG S315T, consistent with multidrug-resistant tuberculosis (MDR-TB) profiles. Nearly 48% showed dual resistance to fluoroquinolones and second-line injectables. Conclusion: This study highlights the predominance of resistance-associated mutations and their co-occurrence patterns in shaping MDR-TB profiles in the study setting. The observed burden of second-line drug resistance underscores the importance of comprehensive resistance testing. These findings support the use of mutation profiling for rapid diagnosis and informed treatment decisions, while emphasizing the need for ongoing local surveillance to guide TB control efforts.