A clinical mutation in uvrA , a DNA repair gene, confers survival advantage to Mycobacterium tuberculosis in the host

Abstract

DNA repair pathways play an essential role in maintaining the genomic integrity of bacteria, and a perturbation in their biological activity helps bacteria survive under duress. In drug-resistant clinical strains, we identified a Q135K mutation in the uvrA gene, a DNA repair pathway gene. To delineate the role of uvrA and the Q135K mutation, we generated the gene replacement mutant of UvrA (RvΔuvrA) in Mycobacterium tuberculosis H37Rv (Mtb-Rv). While the lack of UvrA function in RvΔuvrA could be restored upon complementation with uvrA, the uvrA-Q135K mutant identified in clinical drug-resistant strains failed to do so. This was reflected in higher mutation rates in RvΔuvrA and RvΔuvrA::uvrAQ135A, compared with wild-type Rv or RvΔuvrA::uvrA complemented strains in the presence and absence of oxidative stress. Killing kinetics experiments with anti-TB drugs showed increased survival of RvΔuvrA and RvΔuvrA::uvrAQ135K, strains compared with Rv or RvΔuvrA::uvrA. Importantly, RvΔuvrA and RvΔuvrA::uvrAQ135K showed enhanced survival in peritoneal macrophages and murine infection model of infection. Together, data suggests that acquiring Q135K mutation benefits the pathogen, which helps enhance the host's survival adaptability.