Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes

Abstract Because of the scanty pipeline of antibiotics newly obtained from nature, chemical modification of established drugs is one of the major streams of current antibacterial research. Intuitive and easy-to-use assays are critical for identifying drug candidates with novel modes of action. In th...

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Autores principales:	Atsushi Sugimoto, Asuka Maeda, Kaori Itto, Hirokazu Arimoto
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1d871a2276204003bc1143d9c1499a58
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spelling	oai:doaj.org-article:1d871a2276204003bc1143d9c1499a582021-12-02T15:05:39ZDeciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes10.1038/s41598-017-01267-52045-2322https://doaj.org/article/1d871a2276204003bc1143d9c1499a582017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01267-5https://doaj.org/toc/2045-2322Abstract Because of the scanty pipeline of antibiotics newly obtained from nature, chemical modification of established drugs is one of the major streams of current antibacterial research. Intuitive and easy-to-use assays are critical for identifying drug candidates with novel modes of action. In this study, we demonstrated that metabolic fluorescent staining of growing cell walls is a powerful tool for mode-of-action analyses of antibiotics using Streptococcus pyogenes. A set of major cell-wall-inhibiting antibiotics (bacitracin, d-cycloserine, flavomycin, oxacillin, ramoplanin, and vancomycin) was employed to validate the potential of the assay. The mechanistic differences of these antibiotics were successfully observed. For instance, d-cycloserine treatment induced fluorescently stained, excessive peripheral cell wall growth. This may indicate that the switch from the peripheral growth stage to the succeeding septal growth was disturbed by the treatment. We then applied this assay to analyze a series of vancomycin derivatives. The assay was sufficiently sensitive to detect the effects of single-site chemical modification of vancomycin on its modes of action. This metabolic fluorescent labeling method is easy to perform, especially because it does not require radiolabeled substrates. Thus, it is suitable for the preliminary evaluation of antibacterial mechanisms during antibacterial research.Atsushi SugimotoAsuka MaedaKaori IttoHirokazu ArimotoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Atsushi Sugimoto Asuka Maeda Kaori Itto Hirokazu Arimoto Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes
description	Abstract Because of the scanty pipeline of antibiotics newly obtained from nature, chemical modification of established drugs is one of the major streams of current antibacterial research. Intuitive and easy-to-use assays are critical for identifying drug candidates with novel modes of action. In this study, we demonstrated that metabolic fluorescent staining of growing cell walls is a powerful tool for mode-of-action analyses of antibiotics using Streptococcus pyogenes. A set of major cell-wall-inhibiting antibiotics (bacitracin, d-cycloserine, flavomycin, oxacillin, ramoplanin, and vancomycin) was employed to validate the potential of the assay. The mechanistic differences of these antibiotics were successfully observed. For instance, d-cycloserine treatment induced fluorescently stained, excessive peripheral cell wall growth. This may indicate that the switch from the peripheral growth stage to the succeeding septal growth was disturbed by the treatment. We then applied this assay to analyze a series of vancomycin derivatives. The assay was sufficiently sensitive to detect the effects of single-site chemical modification of vancomycin on its modes of action. This metabolic fluorescent labeling method is easy to perform, especially because it does not require radiolabeled substrates. Thus, it is suitable for the preliminary evaluation of antibacterial mechanisms during antibacterial research.
format	article
author	Atsushi Sugimoto Asuka Maeda Kaori Itto Hirokazu Arimoto
author_facet	Atsushi Sugimoto Asuka Maeda Kaori Itto Hirokazu Arimoto
author_sort	Atsushi Sugimoto
title	Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes
title_short	Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes
title_full	Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes
title_fullStr	Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes
title_full_unstemmed	Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes
title_sort	deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in streptococcus pyogenes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1d871a2276204003bc1143d9c1499a58
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Deciphering the mode of action of cell wall-inhibiting antibiotics using metabolic labeling of growing peptidoglycan in Streptococcus pyogenes

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