Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>
ABSTRACT In Mycobacterium tuberculosis, recent genome-wide association studies have identified a novel constellation of mutations that are correlated with high-level drug resistances. Interpreting the functional importance of the new resistance-associated mutations has been complicated, however, by...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00616-19 |
| _version_ | 1818569461429436416 |
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| author | Nathan D. Hicks Allison F. Carey Jian Yang Yanlin Zhao Sarah M. Fortune |
| author_facet | Nathan D. Hicks Allison F. Carey Jian Yang Yanlin Zhao Sarah M. Fortune |
| author_sort | Nathan D. Hicks |
| collection | DOAJ |
| description | ABSTRACT In Mycobacterium tuberculosis, recent genome-wide association studies have identified a novel constellation of mutations that are correlated with high-level drug resistances. Interpreting the functional importance of the new resistance-associated mutations has been complicated, however, by a lack of experimental validation and a poor understanding of the epistatic factors influencing these correlations, including strain background and programmatic variation in treatment regimens. Here we perform a genome-wide association analysis in a panel of Mycobacterium tuberculosis strains from China to identify variants correlated with resistance to the second-line prodrug ethionamide (ETH). Mutations in a bacterial monooxygenase, Rv0565c, are significantly associated with ETH resistance. We demonstrate that Rv0565c is a novel activator of ETH, independent of the two known activators, EthA and MymA. Clinically prevalent mutations abrogate Rv0565c function, and deletion of Rv0565c confers a consistent fitness benefit on M. tuberculosis in the presence of partially inhibitory doses of ETH. Interestingly, Rv0565c activity affects susceptibility to prothionamide (PTH), the ETH analog used in China, to a greater degree. Further, clinical isolates vary in their susceptibility to both ETH and PTH, to an extent that correlates with the total expression of ETH/PTH activators (EthA, MymA, and Rv0565c). These results suggest that clinical strains considered susceptible to ETH/PTH are not equally fit during treatment due to both Rv0565c mutations and more global variation in the expression of the prodrug activators. IMPORTANCE Phenotypic antibiotic susceptibility testing in Mycobacterium tuberculosis is slow and cumbersome. Rapid molecular diagnostics promise to help guide therapy, but such assays rely on complete knowledge of the molecular determinants of altered antibiotic susceptibility. Recent genomic studies of antibiotic-resistant M. tuberculosis have identified several candidate loci beyond those already known to contribute to antibiotic resistance; however, efforts to provide experimental validation have lagged. Our study identifies a gene (Rv0565c) that is associated with resistance to the second-line antibiotic ethionamide at a population level. We then use bacterial genetics to show that the variants found in clinical strains of M. tuberculosis improve bacterial survival after ethionamide exposure. |
| first_indexed | 2024-12-14T06:48:26Z |
| format | Article |
| id | doaj.art-f930b5b630724c45a84da918597a5194 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T06:48:26Z |
| publishDate | 2019-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-f930b5b630724c45a84da918597a51942022-12-21T23:12:58ZengAmerican Society for MicrobiologymBio2150-75112019-04-0110210.1128/mBio.00616-19Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>Nathan D. Hicks0Allison F. Carey1Jian Yang2Yanlin Zhao3Sarah M. Fortune4Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USADepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USAMOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Centre for Tuberculosis, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaNational Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, ChinaDepartment of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USAABSTRACT In Mycobacterium tuberculosis, recent genome-wide association studies have identified a novel constellation of mutations that are correlated with high-level drug resistances. Interpreting the functional importance of the new resistance-associated mutations has been complicated, however, by a lack of experimental validation and a poor understanding of the epistatic factors influencing these correlations, including strain background and programmatic variation in treatment regimens. Here we perform a genome-wide association analysis in a panel of Mycobacterium tuberculosis strains from China to identify variants correlated with resistance to the second-line prodrug ethionamide (ETH). Mutations in a bacterial monooxygenase, Rv0565c, are significantly associated with ETH resistance. We demonstrate that Rv0565c is a novel activator of ETH, independent of the two known activators, EthA and MymA. Clinically prevalent mutations abrogate Rv0565c function, and deletion of Rv0565c confers a consistent fitness benefit on M. tuberculosis in the presence of partially inhibitory doses of ETH. Interestingly, Rv0565c activity affects susceptibility to prothionamide (PTH), the ETH analog used in China, to a greater degree. Further, clinical isolates vary in their susceptibility to both ETH and PTH, to an extent that correlates with the total expression of ETH/PTH activators (EthA, MymA, and Rv0565c). These results suggest that clinical strains considered susceptible to ETH/PTH are not equally fit during treatment due to both Rv0565c mutations and more global variation in the expression of the prodrug activators. IMPORTANCE Phenotypic antibiotic susceptibility testing in Mycobacterium tuberculosis is slow and cumbersome. Rapid molecular diagnostics promise to help guide therapy, but such assays rely on complete knowledge of the molecular determinants of altered antibiotic susceptibility. Recent genomic studies of antibiotic-resistant M. tuberculosis have identified several candidate loci beyond those already known to contribute to antibiotic resistance; however, efforts to provide experimental validation have lagged. Our study identifies a gene (Rv0565c) that is associated with resistance to the second-line antibiotic ethionamide at a population level. We then use bacterial genetics to show that the variants found in clinical strains of M. tuberculosis improve bacterial survival after ethionamide exposure.https://journals.asm.org/doi/10.1128/mBio.00616-19genome-wide association studyMycobacterium tuberculosisantibiotic resistanceethionamidegenome analysisprothionamide |
| spellingShingle | Nathan D. Hicks Allison F. Carey Jian Yang Yanlin Zhao Sarah M. Fortune Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> mBio genome-wide association study Mycobacterium tuberculosis antibiotic resistance ethionamide genome analysis prothionamide |
| title | Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> |
| title_full | Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> |
| title_fullStr | Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> |
| title_full_unstemmed | Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> |
| title_short | Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> |
| title_sort | bacterial genome wide association identifies novel factors that contribute to ethionamide and prothionamide susceptibility in named content content type genus species mycobacterium tuberculosis named content |
| topic | genome-wide association study Mycobacterium tuberculosis antibiotic resistance ethionamide genome analysis prothionamide |
| url | https://journals.asm.org/doi/10.1128/mBio.00616-19 |
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