Abstract
BACKGROUND: The global spread of rifampicin-resistant tuberculosis (RR-TB) presents a significant challenge to tuberculosis control, with compensatory mutations hypothesized to offset the fitness cost of drug resistance, thereby facilitating transmission. However, the characteristics and epidemiological impact of these mutations in coastal regions of Eastern China remain inadequately understood. This study aimed to characterize the spectrum of compensatory mutations in RR-TB isolates and to assess their association with transmission dynamics in a well-developed coastal region of Eastern China. METHODS: We collected RR-TB cases identified through drug-resistance surveillance in Ningbo, China, from 2021 to 2024. Whole-genome sequencing (WGS) was performed on 180 RR-TB isolates to identify resistance-conferring and compensatory mutations, particularly in the rpoA, rpoB, and rpoC genes. Transmission clusters were inferred using single nucleotide polymorphism (SNP) analysis, and the association between compensatory mutations and the risk of RR-TB clustering was evaluated using logistic regression. RESULTS: Among the 180 RR-TB isolates analyzed, 28.9% harbored putative compensatory mutations, predominantly in rpoC. Isolates with compensatory mutations were significantly more likely to be part of genomic transmission clusters than those without such mutations (odds ratio: 4.28, 95% CI: 2.07-8.85). No significant differences in demographic or clinical characteristics were observed between clustered and non-clustered cases. Phylogenetic analysis indicated ongoing local transmission of compensated RR-TB strains. CONCLUSION: Compensatory mutations are prevalent among RR-TB strains in coastal Eastern China and are strongly associated with increased transmission, underscoring their role in sustaining the RR-TB epidemic in this region. Enhanced molecular surveillance and targeted interventions are warranted to curb the spread of compensated RR-TB.