Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence
Abstract Antimicrobial combination therapy is widely used to combat Mycobacterium tuberculosis (Mtb), yet resistance rates continue to rise. Mutator strains, with defects in DNA repair genes, drive resistance in other bacterial infections, but their role in Mtb remains unclear. Here, we study the co...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | npj Antimicrobials and Resistance |
| Online Access: | https://doi.org/10.1038/s44259-025-00107-1 |
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| author | R. Zein-Eddine A. Le Meur S. Skouloubris L. Jelsbak G. Refrégier H. Myllykallio |
| author_facet | R. Zein-Eddine A. Le Meur S. Skouloubris L. Jelsbak G. Refrégier H. Myllykallio |
| author_sort | R. Zein-Eddine |
| collection | DOAJ |
| description | Abstract Antimicrobial combination therapy is widely used to combat Mycobacterium tuberculosis (Mtb), yet resistance rates continue to rise. Mutator strains, with defects in DNA repair genes, drive resistance in other bacterial infections, but their role in Mtb remains unclear. Here, we study the contribution of single nucleotide polymorphisms (SNPs) in DNA Repair, Replication, and Recombination (3 R) genes to Mtb resistance. Through large-scale bioinformatics analysis of 53,589 whole-genomes, we identified 18 novel SNPs in lineages 2 and 4 linked to genotypic drug resistance in 3 R genes, covering 12.5% of clinical isolates with available genome sequences. Notably, a number of the detected SNPs were positively selected during Mtb evolution. Experimental tests showed that mutM, fpgg2, xthA, and nucS mutants had increased the mutation frequency compared to the wild type. Our findings highlight the role of 3 R gene mutations in resistance, emphasizing the need for surveillance to improve early detection and control strategies. |
| format | Article |
| id | doaj-art-dfa8e7da9644425898f866136191a676 |
| institution | DOAJ |
| issn | 2731-8745 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Antimicrobials and Resistance |
| spelling | doaj-art-dfa8e7da9644425898f866136191a6762025-08-20T02:55:24ZengNature Portfolionpj Antimicrobials and Resistance2731-87452025-04-013111010.1038/s44259-025-00107-1Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergenceR. Zein-Eddine0A. Le Meur1S. Skouloubris2L. Jelsbak3G. Refrégier4H. Myllykallio5Laboratoire d’Optique et Biosciences (LOB), Ecole Polytechnique, Inserm U1182, CNRS UMR7645, Institut Polytechnique de ParisLaboratoire d’Ecologie Systématique et Evolution, CNRS UMR8079, AgroParisTechLaboratoire d’Optique et Biosciences (LOB), Ecole Polytechnique, Inserm U1182, CNRS UMR7645, Institut Polytechnique de ParisDepartment of Biotechnology and Biomedicine, Technical University of DenmarkLaboratoire d’Ecologie Systématique et Evolution, CNRS UMR8079, AgroParisTechLaboratoire d’Optique et Biosciences (LOB), Ecole Polytechnique, Inserm U1182, CNRS UMR7645, Institut Polytechnique de ParisAbstract Antimicrobial combination therapy is widely used to combat Mycobacterium tuberculosis (Mtb), yet resistance rates continue to rise. Mutator strains, with defects in DNA repair genes, drive resistance in other bacterial infections, but their role in Mtb remains unclear. Here, we study the contribution of single nucleotide polymorphisms (SNPs) in DNA Repair, Replication, and Recombination (3 R) genes to Mtb resistance. Through large-scale bioinformatics analysis of 53,589 whole-genomes, we identified 18 novel SNPs in lineages 2 and 4 linked to genotypic drug resistance in 3 R genes, covering 12.5% of clinical isolates with available genome sequences. Notably, a number of the detected SNPs were positively selected during Mtb evolution. Experimental tests showed that mutM, fpgg2, xthA, and nucS mutants had increased the mutation frequency compared to the wild type. Our findings highlight the role of 3 R gene mutations in resistance, emphasizing the need for surveillance to improve early detection and control strategies.https://doi.org/10.1038/s44259-025-00107-1 |
| spellingShingle | R. Zein-Eddine A. Le Meur S. Skouloubris L. Jelsbak G. Refrégier H. Myllykallio Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence npj Antimicrobials and Resistance |
| title | Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence |
| title_full | Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence |
| title_fullStr | Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence |
| title_full_unstemmed | Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence |
| title_short | Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence |
| title_sort | genome wide analyses reveal the role of mutator phenotypes in mycobacterium tuberculosis drug resistance emergence |
| url | https://doi.org/10.1038/s44259-025-00107-1 |
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