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

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 know...

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Autores principales: Naz, Saba, Paritosh, Kumar, Sanyal, Priyadarshini, Khan, Sidra, Singh, Yogendra, Varshney, Umesh, Nandicoori, Vinay Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9876569/
https://www.ncbi.nlm.nih.gov/pubmed/36695572
http://dx.doi.org/10.7554/eLife.75860
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author Naz, Saba
Paritosh, Kumar
Sanyal, Priyadarshini
Khan, Sidra
Singh, Yogendra
Varshney, Umesh
Nandicoori, Vinay Kumar
author_facet Naz, Saba
Paritosh, Kumar
Sanyal, Priyadarshini
Khan, Sidra
Singh, Yogendra
Varshney, Umesh
Nandicoori, Vinay Kumar
author_sort Naz, Saba
collection PubMed
description 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 knockouts 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.
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spelling pubmed-98765692023-01-26 GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis Naz, Saba Paritosh, Kumar Sanyal, Priyadarshini Khan, Sidra Singh, Yogendra Varshney, Umesh Nandicoori, Vinay Kumar eLife Microbiology and Infectious Disease 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 knockouts 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. eLife Sciences Publications, Ltd 2023-01-25 /pmc/articles/PMC9876569/ /pubmed/36695572 http://dx.doi.org/10.7554/eLife.75860 Text en © 2023, Naz, Paritosh et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Naz, Saba
Paritosh, Kumar
Sanyal, Priyadarshini
Khan, Sidra
Singh, Yogendra
Varshney, Umesh
Nandicoori, Vinay Kumar
GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
title GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
title_full GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
title_fullStr GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
title_full_unstemmed GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
title_short GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
title_sort gwas and functional studies suggest a role for altered dna repair in the evolution of drug resistance in mycobacterium tuberculosis
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9876569/
https://www.ncbi.nlm.nih.gov/pubmed/36695572
http://dx.doi.org/10.7554/eLife.75860
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