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...

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Autores principales:	Nathan D. Hicks, Allison F. Carey, Jian Yang, Yanlin Zhao, Sarah M. Fortune
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	genome-wide association study Mycobacterium tuberculosis antibiotic resistance ethionamide genome analysis prothionamide Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f930b5b630724c45a84da918597a5194
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spelling	oai:doaj.org-article:f930b5b630724c45a84da918597a51942021-11-15T15:55:25ZBacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content>10.1128/mBio.00616-192150-7511https://doaj.org/article/f930b5b630724c45a84da918597a51942019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00616-19https://doaj.org/toc/2150-7511ABSTRACT 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.Nathan D. HicksAllison F. CareyJian YangYanlin ZhaoSarah M. FortuneAmerican Society for Microbiologyarticlegenome-wide association studyMycobacterium tuberculosisantibiotic resistanceethionamidegenome analysisprothionamideMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	genome-wide association study Mycobacterium tuberculosis antibiotic resistance ethionamide genome analysis prothionamide Microbiology QR1-502
spellingShingle	genome-wide association study Mycobacterium tuberculosis antibiotic resistance ethionamide genome analysis prothionamide Microbiology QR1-502 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>
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.
format	article
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
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_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_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_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>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/f930b5b630724c45a84da918597a5194
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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>

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