Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways

ABSTRACT A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in Mycobacterium tuberculosis, the major causative agent of tuberculosis, usi...

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Autores principales:	Yusuke Minato, Daryl M. Gohl, Joshua M. Thiede, Jeremy M. Chacón, William R. Harcombe, Fumito Maruyama, Anthony D. Baughn
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	comparative genomics metabolic modeling metabolism Tn-seq tuberculosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ad5d108f32c64e50b9dd00178fb3a8e5
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spelling	oai:doaj.org-article:ad5d108f32c64e50b9dd00178fb3a8e52021-12-02T18:39:47ZGenomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways10.1128/mSystems.00070-192379-5077https://doaj.org/article/ad5d108f32c64e50b9dd00178fb3a8e52019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00070-19https://doaj.org/toc/2379-5077ABSTRACT A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in Mycobacterium tuberculosis, the major causative agent of tuberculosis, using a combination of transposon insertion sequencing (Tn-seq) and comparative genomic analysis. To identify conditionally essential genes by Tn-seq, we used media with different nutrient compositions. Although many conditional gene essentialities were affected by the presence of relevant nutrient sources, we also found that the essentiality of genes in a subset of metabolic pathways was unaffected by metabolite availability. Comparative genomic analysis revealed that not all essential genes identified by Tn-seq were fully conserved within the M. tuberculosis complex, including some existing antitubercular drug target genes. In addition, we utilized an available M. tuberculosis genome-scale metabolic model, iSM810, to predict M. tuberculosis gene essentiality in silico. Comparing the sets of essential genes experimentally identified by Tn-seq to those predicted in silico reveals the capabilities and limitations of gene essentiality predictions, highlighting the complexity of M. tuberculosis essential metabolic functions. This study provides a promising platform to study essential cellular functions in M. tuberculosis. IMPORTANCE Mycobacterium tuberculosis causes 10 million cases of tuberculosis (TB), resulting in over 1 million deaths each year. TB therapy is challenging because it requires a minimum of 6 months of treatment with multiple drugs. Protracted treatment times and the emergent spread of drug-resistant M. tuberculosis necessitate the identification of novel targets for drug discovery to curb this global health threat. Essential functions, defined as those indispensable for growth and/or survival, are potential targets for new antimicrobial drugs. In this study, we aimed to define gene essentialities of M. tuberculosis on a genomewide scale to comprehensively identify potential targets for drug discovery. We utilized a combination of experimental (functional genomics) and in silico approaches (comparative genomics and flux balance analysis). Our functional genomics approach identified sets of genes whose essentiality was affected by nutrient availability. Comparative genomics revealed that not all essential genes were fully conserved within the M. tuberculosis complex. Comparing sets of essential genes identified by functional genomics to those predicted by flux balance analysis highlighted gaps in current knowledge regarding M. tuberculosis metabolic capabilities. Thus, our study identifies numerous potential antitubercular drug targets and provides a comprehensive picture of the complexity of M. tuberculosis essential cellular functions.Yusuke MinatoDaryl M. GohlJoshua M. ThiedeJeremy M. ChacónWilliam R. HarcombeFumito MaruyamaAnthony D. BaughnAmerican Society for Microbiologyarticlecomparative genomicsmetabolic modelingmetabolismTn-seqtuberculosisMicrobiologyQR1-502ENmSystems, Vol 4, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	comparative genomics metabolic modeling metabolism Tn-seq tuberculosis Microbiology QR1-502
spellingShingle	comparative genomics metabolic modeling metabolism Tn-seq tuberculosis Microbiology QR1-502 Yusuke Minato Daryl M. Gohl Joshua M. Thiede Jeremy M. Chacón William R. Harcombe Fumito Maruyama Anthony D. Baughn Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways
description	ABSTRACT A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in Mycobacterium tuberculosis, the major causative agent of tuberculosis, using a combination of transposon insertion sequencing (Tn-seq) and comparative genomic analysis. To identify conditionally essential genes by Tn-seq, we used media with different nutrient compositions. Although many conditional gene essentialities were affected by the presence of relevant nutrient sources, we also found that the essentiality of genes in a subset of metabolic pathways was unaffected by metabolite availability. Comparative genomic analysis revealed that not all essential genes identified by Tn-seq were fully conserved within the M. tuberculosis complex, including some existing antitubercular drug target genes. In addition, we utilized an available M. tuberculosis genome-scale metabolic model, iSM810, to predict M. tuberculosis gene essentiality in silico. Comparing the sets of essential genes experimentally identified by Tn-seq to those predicted in silico reveals the capabilities and limitations of gene essentiality predictions, highlighting the complexity of M. tuberculosis essential metabolic functions. This study provides a promising platform to study essential cellular functions in M. tuberculosis. IMPORTANCE Mycobacterium tuberculosis causes 10 million cases of tuberculosis (TB), resulting in over 1 million deaths each year. TB therapy is challenging because it requires a minimum of 6 months of treatment with multiple drugs. Protracted treatment times and the emergent spread of drug-resistant M. tuberculosis necessitate the identification of novel targets for drug discovery to curb this global health threat. Essential functions, defined as those indispensable for growth and/or survival, are potential targets for new antimicrobial drugs. In this study, we aimed to define gene essentialities of M. tuberculosis on a genomewide scale to comprehensively identify potential targets for drug discovery. We utilized a combination of experimental (functional genomics) and in silico approaches (comparative genomics and flux balance analysis). Our functional genomics approach identified sets of genes whose essentiality was affected by nutrient availability. Comparative genomics revealed that not all essential genes were fully conserved within the M. tuberculosis complex. Comparing sets of essential genes identified by functional genomics to those predicted by flux balance analysis highlighted gaps in current knowledge regarding M. tuberculosis metabolic capabilities. Thus, our study identifies numerous potential antitubercular drug targets and provides a comprehensive picture of the complexity of M. tuberculosis essential cellular functions.
format	article
author	Yusuke Minato Daryl M. Gohl Joshua M. Thiede Jeremy M. Chacón William R. Harcombe Fumito Maruyama Anthony D. Baughn
author_facet	Yusuke Minato Daryl M. Gohl Joshua M. Thiede Jeremy M. Chacón William R. Harcombe Fumito Maruyama Anthony D. Baughn
author_sort	Yusuke Minato
title	Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways
title_short	Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways
title_full	Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways
title_fullStr	Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways
title_full_unstemmed	Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways
title_sort	genomewide assessment of <named-content content-type="genus-species">mycobacterium tuberculosis</named-content> conditionally essential metabolic pathways
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ad5d108f32c64e50b9dd00178fb3a8e5
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Genomewide Assessment of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> Conditionally Essential Metabolic Pathways

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