Anders Norman (@micronorman.bsky.social)

Genome wide analyses reveal the role of mutator phenotypes in the emergence of drug resistance in Mycobacterium tuberculosis Antimicrobial combination therapy is widely used to combat Mycobacterium tuberculosis ( Mtb ), yet resistance rates continue to rise. Mutator strains, with defects in DNA repair genes, are a known source of resistance in other bacterial infections, but their global role in Mtb remains unclear. Here, we provide a comprehensive overview of the contribution of single nucleotide polymorphisms (SNPs) in DNA Repair, Replication, and Recombination (3R) genes to resistance in Mtb . Through large-scale bioinformatics analysis of 53,589 whole-genomes, we identified 18 novel SNPs linked to genotypic drug resistance in 3R genes, covering 12.5% of clinical isolates/strains with available genome sequences. Notably, a number of the detected SNPs were positively selected during Mtb evolution. Experimental mutation frequency tests further indicated functional defects of these sequence variants in key DNA repair pathways. Our findings indicate that the role of mutability in 3R genes plays a significant role in Mtb resistance at the global level. ### Competing Interest Statement The authors have declared no competing interest. https://www.biorxiv.org/content/10.1101/2025.01.17.633521v1