Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence

ABSTRACT Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel ant...

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Autores principales:	Muyoung Lee, Naina Adren Pinto, Chan Yeong Kim, Sunmo Yang, Roshan D’Souza, Dongeun Yong, Insuk Lee
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Klebsiella pneumoniae antimicrobial resistance carbapenem gene network virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/777f2a675b754d3e851442b97880576c
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spelling	oai:doaj.org-article:777f2a675b754d3e851442b97880576c2021-12-02T18:25:16ZNetwork Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence10.1128/mSystems.00202-192379-5077https://doaj.org/article/777f2a675b754d3e851442b97880576c2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00202-19https://doaj.org/toc/2379-5077ABSTRACT Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network of K. pneumoniae genes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence in Galleria mellonella larvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria. IMPORTANCE Klebsiella pneumoniae is a major bacterial pathogen that causes pneumonia and urinary tract infections in human. K. pneumoniae infections are treated with carbapenem, but carbapenem-resistant K. pneumoniae has been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network of K. pneumoniae genes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study of K. pneumoniae infection.Muyoung LeeNaina Adren PintoChan Yeong KimSunmo YangRoshan D’SouzaDongeun YongInsuk LeeAmerican Society for MicrobiologyarticleKlebsiella pneumoniaeantimicrobial resistancecarbapenemgene networkvirulenceMicrobiologyQR1-502ENmSystems, Vol 4, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Klebsiella pneumoniae antimicrobial resistance carbapenem gene network virulence Microbiology QR1-502
spellingShingle	Klebsiella pneumoniae antimicrobial resistance carbapenem gene network virulence Microbiology QR1-502 Muyoung Lee Naina Adren Pinto Chan Yeong Kim Sunmo Yang Roshan D’Souza Dongeun Yong Insuk Lee Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence
description	ABSTRACT Global increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network of K. pneumoniae genes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence in Galleria mellonella larvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria. IMPORTANCE Klebsiella pneumoniae is a major bacterial pathogen that causes pneumonia and urinary tract infections in human. K. pneumoniae infections are treated with carbapenem, but carbapenem-resistant K. pneumoniae has been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network of K. pneumoniae genes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study of K. pneumoniae infection.
format	article
author	Muyoung Lee Naina Adren Pinto Chan Yeong Kim Sunmo Yang Roshan D’Souza Dongeun Yong Insuk Lee
author_facet	Muyoung Lee Naina Adren Pinto Chan Yeong Kim Sunmo Yang Roshan D’Souza Dongeun Yong Insuk Lee
author_sort	Muyoung Lee
title	Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence
title_short	Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence
title_full	Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence
title_fullStr	Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence
title_full_unstemmed	Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence
title_sort	network integrative genomic and transcriptomic analysis of carbapenem-resistant <named-content content-type="genus-species">klebsiella pneumoniae</named-content> strains identifies genes for antibiotic resistance and virulence
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/777f2a675b754d3e851442b97880576c
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Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-Resistant <named-content content-type="genus-species">Klebsiella pneumoniae</named-content> Strains Identifies Genes for Antibiotic Resistance and Virulence

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