Abstract
Background/Objectives: Multidrug-resistant tuberculosis remains a critical public health challenge in Kazakhstan, yet the genomic determinants contributing to its emergence are still insufficiently understood. Although the quantity of genomic studies from Central Asia and the wider post-Soviet region has increased in recent years, the involvement of DNA repair and genome maintenance pathways in the development of resistance within Kazakhstan has not been comprehensively explored. Methods: In this study, we performed whole-genome analysis of 175 Mycobacterium tuberculosis clinical isolates collected across Kazakhstan between 2010 and 2022 to evaluate the contribution of single-nucleotide polymorphisms in DNA replication, repair, and recombination (3R) genes to the evolution of drug resistance. Results: Alongside well-established resistance mutations in gyrA, we identified recurrent variants in 3R-associated loci (genes involved in DNA replication, repair, and recombination)—including polA, uvrC and ligC—that were enriched among drug-resistant isolates, suggesting a broader role for genome maintenance pathways in facilitating resistance evolution under treatment pressure. Conclusions: These findings provide the first region-specific genomic insights into 3R gene variation in Kazakhstani M. tuberculosis isolates.