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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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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. |
format | Online Article Text |
id | pubmed-9876569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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