DRUG RESISTANCE AND ITS EFFECT ON THE FITNESS OF MYCOBACTERIUM TUBERCULOSIS: A Review

  Background: The rise of drug-resistant tuberculosis (TB) poses a critical challenge to global TB control efforts, with multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains complicating treatment outcomes. The fitness cost associated with drug resistance mutations, along with compensatory mechanisms, influences transmission dynamics and disease progression. Understanding the epidemiology, bacterial adaptations, and treatment challenges of drug-resistant TB is essential for developing effective therapeutic strategies and mitigating further spread, particularly in high-burden regions with limited access to advanced diagnostics. Objective: This study aims to evaluate the impact of drug resistance on Mycobacterium tuberculosis fitness, transmission potential, and treatment outcomes, with a focus on multidrug-resistant and extensively drug-resistant TB cases. The findings will help inform clinical management strategies and enhance efforts toward effective disease control. Methods: A retrospective cohort study was conducted, analyzing 2,142 confirmed pulmonary TB cases over a five-year period. Drug susceptibility testing (DST) was performed using GeneXpert MTB/RIF, line probe assay (LPA), and culture-based methods. Bacterial fitness was assessed through competitive growth assays, while whole-genome sequencing (WGS) identified resistance mutations and compensatory adaptations. Transmission dynamics were examined through spoligotyping and MIRU-VNTR genotyping, with epidemiological data collected through hospital records and patient interviews. Treatment outcomes, including cure rates, failure rates, relapse, and mortality, were compared between drug-susceptible, MDR-TB, and XDR-TB groups. Statistical analyses included odds ratio (OR), Kaplan-Meier survival analysis, and logistic regression modeling, with a significance threshold of p<0.05. Results: Among the 2,142 TB cases, 321 were identified as MDR-TB, 62 developed acquired resistance, and 67 were classified as non-tuberculous mycobacteria (NTM) infections. MDR-TB patients exhibited lower cure rates and higher treatment failure compared to drug-susceptible TB cases (p<0.001). Whole-genome sequencing revealed rpoB mutations (Ser531Leu, His526Tyr) in 87% of rifampicin-resistant isolates and katG Ser315Thr mutations in 81% of isoniazid-resistant strains. XDR-TB strains demonstrated a 25% reduction in bacterial replication rates compared to MDR-TB strains in antibiotic-free environments, yet 40% of XDR-TB isolates exhibited compensatory rpoC mutations restoring fitness. Transmission analysis indicated MDR-TB strains were 2.3 times more likely to cluster compared to XDR-TB strains (p=0.012), suggesting reduced transmissibility of highly resistant strains. Treatment adherence was significantly lower in MDR-TB and XDR-TB groups, with XDR-TB patients experiencing a 3.1-fold higher likelihood of discontinuation due to adverse effects (p<0.001). Conclusion: The findings highlight the complex interplay between bacterial fitness, transmission potential, and treatment challenges in drug-resistant TB. While MDR and XDR-TB strains initially experience a fitness cost, compensatory mutations restore their viability, influencing long-term persistence and spread. The high rates of treatment failure, prolonged therapy duration, and adverse effects contribute to poor patient adherence and continued transmission. Strengthening genomic surveillance, optimizing therapeutic strategies, and implementing patient-centered adherence programs is essential for effective TB control and prevention of further resistance evolution.