Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis
Abstract Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in the katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate colla...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54072-w |
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| author | XinYue Wang William J. Jowsey Chen-Yi Cheung Caitlan J. Smart Hannah R. Klaus Noon EJ Seeto Natalie JE Waller Michael T. Chrisp Amanda L. Peterson Boatema Ofori-Anyinam Emily Strong Brunda Nijagal Nicholas P. West Jason H. Yang Peter C. Fineran Gregory M. Cook Simon A. Jackson Matthew B. McNeil |
| author_facet | XinYue Wang William J. Jowsey Chen-Yi Cheung Caitlan J. Smart Hannah R. Klaus Noon EJ Seeto Natalie JE Waller Michael T. Chrisp Amanda L. Peterson Boatema Ofori-Anyinam Emily Strong Brunda Nijagal Nicholas P. West Jason H. Yang Peter C. Fineran Gregory M. Cook Simon A. Jackson Matthew B. McNeil |
| author_sort | XinYue Wang |
| collection | DOAJ |
| description | Abstract Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in the katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities in isoniazid-resistant katG mutants, providing potential pathway targets to combat isoniazid resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used to generate a genome-wide map of cellular vulnerabilities in an isoniazid-resistant katG mutant strain of M. tuberculosis. Here, we show that metabolic and transcriptional remodelling compensates for the loss of KatG but in doing so generates vulnerabilities in respiration, ribosome biogenesis, and nucleotide and amino acid metabolism. Importantly, these vulnerabilities are more sensitive to inhibition in an isoniazid-resistant katG mutant and translated to clinical isolates. This work highlights how changes in the physiology of drug-resistant strains generates druggable vulnerabilities that can be exploited to improve clinical outcomes. |
| format | Article |
| id | doaj-art-138d2c76fe9b40538e5e763113a839ee |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-138d2c76fe9b40538e5e763113a839ee2024-11-17T12:36:40ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54072-wWhole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosisXinYue Wang0William J. Jowsey1Chen-Yi Cheung2Caitlan J. Smart3Hannah R. Klaus4Noon EJ Seeto5Natalie JE Waller6Michael T. Chrisp7Amanda L. Peterson8Boatema Ofori-Anyinam9Emily Strong10Brunda Nijagal11Nicholas P. West12Jason H. Yang13Peter C. Fineran14Gregory M. Cook15Simon A. Jackson16Matthew B. McNeil17Department of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoMetabolomics Australia, Bio21 Institute, The University of MelbourneCenter for Emerging and Re-emerging Pathogens, Public Health Research Institute, Rutgers New Jersey Medical SchoolSchool of Chemistry and Molecular Biosciences, The University of QueenslandMetabolomics Australia, Bio21 Institute, The University of MelbourneSchool of Chemistry and Molecular Biosciences, The University of QueenslandCenter for Emerging and Re-emerging Pathogens, Public Health Research Institute, Rutgers New Jersey Medical SchoolDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoDepartment of Microbiology and Immunology, University of OtagoAbstract Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in the katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities in isoniazid-resistant katG mutants, providing potential pathway targets to combat isoniazid resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used to generate a genome-wide map of cellular vulnerabilities in an isoniazid-resistant katG mutant strain of M. tuberculosis. Here, we show that metabolic and transcriptional remodelling compensates for the loss of KatG but in doing so generates vulnerabilities in respiration, ribosome biogenesis, and nucleotide and amino acid metabolism. Importantly, these vulnerabilities are more sensitive to inhibition in an isoniazid-resistant katG mutant and translated to clinical isolates. This work highlights how changes in the physiology of drug-resistant strains generates druggable vulnerabilities that can be exploited to improve clinical outcomes.https://doi.org/10.1038/s41467-024-54072-w |
| spellingShingle | XinYue Wang William J. Jowsey Chen-Yi Cheung Caitlan J. Smart Hannah R. Klaus Noon EJ Seeto Natalie JE Waller Michael T. Chrisp Amanda L. Peterson Boatema Ofori-Anyinam Emily Strong Brunda Nijagal Nicholas P. West Jason H. Yang Peter C. Fineran Gregory M. Cook Simon A. Jackson Matthew B. McNeil Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis Nature Communications |
| title | Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis |
| title_full | Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis |
| title_fullStr | Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis |
| title_full_unstemmed | Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis |
| title_short | Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis |
| title_sort | whole genome crispri screening identifies druggable vulnerabilities in an isoniazid resistant strain of mycobacterium tuberculosis |
| url | https://doi.org/10.1038/s41467-024-54072-w |
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