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GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis

Naz, S and Paritosh, K and Sanyal, P and Khan, S and Singh, Y and Varshney, U and Nandicoori, VK (2023) GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis. In: eLife, 12 .

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Official URL: https://doi.org/10.7554/eLife.75860


The emergence of drug resistance in Mycobacterium tuberculosis (Mtb) is alarming and demands in-depth knowledge for timely diagnosis. We performed genome-wide association analysis using 2237 clinical strains of Mtb 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 knock-outs and complemented strains in Mycobacterium smegmatis and Mtb. Results show that variant mutations compromised the functions of MutY and UvrB. MutY variant showed enhanced survival compared with wild-type (Rv) when the Mtb 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. © Naz, Paritosh et al.

Item Type: Journal Article
Publication: eLife
Publisher: eLife Sciences Publications Ltd
Additional Information: The copyright for this article belongs to eLife Sciences Publications Ltd.
Keywords: tuberculostatic agent, animal; DNA repair; genetics; genome-wide association study; guinea pig; microbial sensitivity test; microbiology; multidrug resistance; multidrug resistant tuberculosis; mutation; Mycobacterium tuberculosis, Animals; Antitubercular Agents; DNA Repair; Drug Resistance, Multiple, Bacterial; Genome-Wide Association Study; Guinea Pigs; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 16 Feb 2023 05:25
Last Modified: 16 Feb 2023 05:25
URI: https://eprints.iisc.ac.in/id/eprint/80310

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