Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance

ABSTRACT Teixobactin is a new antimicrobial of significant interest. It is active against a number of multidrug-resistant pathogens, including Staphylococcus aureus and Enterococcus faecalis, with no reported mechanisms of teixobactin resistance. However, historically, mechanisms of resistance alway...

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Autores principales:	Rachel L. Darnell, Melanie K. Knottenbelt, Francesca O. Todd Rose, Ian R. Monk, Timothy P. Stinear, Gregory M. Cook
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	CroRS Enterococcus RNA sequencing teixobactin antimicrobial resistance antimicrobial tolerance Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c50567fb76cb42369d772605e2894761
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spelling	oai:doaj.org-article:c50567fb76cb42369d772605e28947612021-11-15T15:22:20ZGenomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance10.1128/mSphere.00228-192379-5042https://doaj.org/article/c50567fb76cb42369d772605e28947612019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00228-19https://doaj.org/toc/2379-5042ABSTRACT Teixobactin is a new antimicrobial of significant interest. It is active against a number of multidrug-resistant pathogens, including Staphylococcus aureus and Enterococcus faecalis, with no reported mechanisms of teixobactin resistance. However, historically, mechanisms of resistance always exist and arise upon introduction of a new antimicrobial into a clinical setting. Therefore, for teixobactin to remain effective long term, we need to understand how mechanisms of resistance could develop. Here we demonstrate that E. faecalis shows a remarkable intrinsic tolerance to high concentrations of teixobactin. This is of critical importance, as antimicrobial tolerance has been shown to precede the development of antimicrobial resistance. To identify potential pathways responsible for this tolerance, we determined the genomewide expression profile of E. faecalis strain JH2-2 in response to teixobactin using RNA sequencing. A total of 573 genes were differentially expressed (2.0-fold log2 change in expression) in response to teixobactin, with genes involved in cell wall biogenesis and division and transport/binding being among those that were the most upregulated. Comparative analyses of E. faecalis cell wall-targeting antimicrobial transcriptomes identified CroRS, LiaRS, and YclRK to be important two-component regulators of antimicrobial-mediated stress. Further investigation of CroRS demonstrated that deletion of croRS abolished tolerance to teixobactin and to other cell wall-targeting antimicrobials. This highlights the crucial role of CroRS in controlling the molecular response to teixobactin. IMPORTANCE Teixobactin is a new antimicrobial with no known mechanisms of resistance. Understanding how resistance could develop will be crucial to the success and longevity of teixobactin as a new potent antimicrobial. Antimicrobial tolerance has been shown to facilitate the development of resistance, and we show that E. faecalis is intrinsically tolerant to teixobactin at high concentrations. We subsequently chose E. faecalis as a model to elucidate the molecular mechanism underpinning teixobactin tolerance and how this may contribute to the development of teixobactin resistance.Rachel L. DarnellMelanie K. KnottenbeltFrancesca O. Todd RoseIan R. MonkTimothy P. StinearGregory M. CookAmerican Society for MicrobiologyarticleCroRSEnterococcusRNA sequencingteixobactinantimicrobial resistanceantimicrobial toleranceMicrobiologyQR1-502ENmSphere, Vol 4, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	CroRS Enterococcus RNA sequencing teixobactin antimicrobial resistance antimicrobial tolerance Microbiology QR1-502
spellingShingle	CroRS Enterococcus RNA sequencing teixobactin antimicrobial resistance antimicrobial tolerance Microbiology QR1-502 Rachel L. Darnell Melanie K. Knottenbelt Francesca O. Todd Rose Ian R. Monk Timothy P. Stinear Gregory M. Cook Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance
description	ABSTRACT Teixobactin is a new antimicrobial of significant interest. It is active against a number of multidrug-resistant pathogens, including Staphylococcus aureus and Enterococcus faecalis, with no reported mechanisms of teixobactin resistance. However, historically, mechanisms of resistance always exist and arise upon introduction of a new antimicrobial into a clinical setting. Therefore, for teixobactin to remain effective long term, we need to understand how mechanisms of resistance could develop. Here we demonstrate that E. faecalis shows a remarkable intrinsic tolerance to high concentrations of teixobactin. This is of critical importance, as antimicrobial tolerance has been shown to precede the development of antimicrobial resistance. To identify potential pathways responsible for this tolerance, we determined the genomewide expression profile of E. faecalis strain JH2-2 in response to teixobactin using RNA sequencing. A total of 573 genes were differentially expressed (2.0-fold log2 change in expression) in response to teixobactin, with genes involved in cell wall biogenesis and division and transport/binding being among those that were the most upregulated. Comparative analyses of E. faecalis cell wall-targeting antimicrobial transcriptomes identified CroRS, LiaRS, and YclRK to be important two-component regulators of antimicrobial-mediated stress. Further investigation of CroRS demonstrated that deletion of croRS abolished tolerance to teixobactin and to other cell wall-targeting antimicrobials. This highlights the crucial role of CroRS in controlling the molecular response to teixobactin. IMPORTANCE Teixobactin is a new antimicrobial with no known mechanisms of resistance. Understanding how resistance could develop will be crucial to the success and longevity of teixobactin as a new potent antimicrobial. Antimicrobial tolerance has been shown to facilitate the development of resistance, and we show that E. faecalis is intrinsically tolerant to teixobactin at high concentrations. We subsequently chose E. faecalis as a model to elucidate the molecular mechanism underpinning teixobactin tolerance and how this may contribute to the development of teixobactin resistance.
format	article
author	Rachel L. Darnell Melanie K. Knottenbelt Francesca O. Todd Rose Ian R. Monk Timothy P. Stinear Gregory M. Cook
author_facet	Rachel L. Darnell Melanie K. Knottenbelt Francesca O. Todd Rose Ian R. Monk Timothy P. Stinear Gregory M. Cook
author_sort	Rachel L. Darnell
title	Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance
title_short	Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance
title_full	Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance
title_fullStr	Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance
title_full_unstemmed	Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance
title_sort	genomewide profiling of the <named-content content-type="genus-species">enterococcus faecalis</named-content> transcriptional response to teixobactin reveals crors as an essential regulator of antimicrobial tolerance
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/c50567fb76cb42369d772605e2894761
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Genomewide Profiling of the <named-content content-type="genus-species">Enterococcus faecalis</named-content> Transcriptional Response to Teixobactin Reveals CroRS as an Essential Regulator of Antimicrobial Tolerance

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