GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in <i>Mycobacterium tuberculosis</i>.

Abstract

The emergence of drug resistance in <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is alarming and demands in-depth knowledge for timely diagnosis. We performed genome-wide association analysis using 2237 clinical strains of <i>Mtb</i> to identify novel genetic factors that evoke drug resistance. In addition to the known direct targets, we identified for the first time, a strong association between mutations in DNA repair genes and the multidrug-resistant phenotype. To evaluate the impact of variants identified in the clinical samples in the evolution of drug resistance, we utilized knockouts and complemented strains in <i>Mycobacterium smegmatis</i> and <i>Mtb</i>. Results show that variant mutations compromised the functions of MutY and UvrB. MutY variant showed enhanced survival compared with wild-type (<i>Rv</i>) when the <i>Mtb</i> strains were subjected to multiple rounds of ex vivo antibiotic stress. In an in vivo guinea pig infection model, the MutY variant outcompeted the wild-type strain. We show that novel variant mutations in the DNA repair genes collectively compromise their functions and contribute to better survival under antibiotic/host stress conditions.