Mutator gene defects fuel global tuberculosis drug resistance

Tuberculosis remains a major global health challenge, and clinicians commonly use antimicrobial combination therapy to treat infections caused by Mycobacterium tuberculosis (Mtb). Despite these treatment strategies, resistance to drugs continues to rise, undermining control efforts. One possible source of resistance is so-called mutator strains: bacteria with defects in DNA repair genes that make them more likely to acquire mutations, including mutations that confer drug resistance. Mutator strains are a known contributor to resistance in other bacterial infections, but until now their role in Mtb on a global scale was not clear. To address this gap, a large research effort led by Rima Zein-Eddine set out to look across thousands of Mtb genomes for single nucleotide polymorphisms (SNPs) in DNA Repair, Replication, and Recombination (3R) genes. The goal was to determine whether variation in these genes is linked to genotypic drug resistance and whether such variants have been favored during Mtb evolution. By focusing on 3R genes, the team aimed to reveal whether intrinsic changes to the bacterium’s ability to maintain or repair its DNA are contributing to the emergence and spread of drug-resistant tuberculosis.

The researchers used a large-scale bioinformatics analysis of 53,589 whole-genomes of Mycobacterium tuberculosis to search for associations between sequence variation in DNA Repair, Replication, and Recombination (3R) genes and genotypic drug resistance. This genome-wide screen identified 18 novel single nucleotide polymorphisms (SNPs) in 3R genes that are linked to genotypic drug resistance. Altogether, these sequence variants appeared in 12.5% of clinical isolates/strains with available genome sequences, indicating a substantial presence in the sampled global population. Evolutionary analyses showed that a number of the detected SNPs were positively selected during Mtb evolution, suggesting that they conferred a benefit to the bacteria. To test whether these variants actually affected mutation rates, the team performed experimental mutation frequency tests, which indicated functional defects of these sequence variants in key DNA repair pathways. Taken together, the combination of large-scale genomic screening and laboratory mutation frequency tests supports the idea that defects in 3R genes can increase mutability and are associated with drug-resistant Mtb.

These findings point to a meaningful role for mutability driven by changes in DNA Repair, Replication, and Recombination genes in the emergence and spread of drug resistance in Mycobacterium tuberculosis at a global level. If defects in 3R genes make Mtb more likely to acquire resistance-conferring mutations, that could help explain why resistance continues to emerge even under antimicrobial combination therapy. Recognizing 3R gene variants as contributors to resistance changes the way researchers and public health programs might think about surveillance: tracking SNPs in DNA repair pathways could reveal strains with heightened potential to become resistant. The results also highlight the importance of combining genomic surveillance with functional laboratory tests, because finding a variant in a sequence database is strengthened when experimental work shows it affects mutation frequency. Overall, the study led by Rima Zein-Eddine suggests that monitoring and studying mutator phenotypes should be part of broader efforts to understand, predict, and ultimately limit the rise of drug-resistant tuberculosis.