Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria

Abstract Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural analysis of vancomycin-Zn(II) crystals and fibre X-ray diffraction. Bioassays indicate that this structure is associated wi...

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Autores principales:	Ashraf Zarkan, Heather-Rose Macklyne, Dimitri Y. Chirgadze, Andrew D. Bond, Andrew R. Hesketh, Hee-Jeon Hong
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/36da0b6203544be3912a0cf3797ab0ad
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spelling	oai:doaj.org-article:36da0b6203544be3912a0cf3797ab0ad2021-12-02T12:30:35ZZn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria10.1038/s41598-017-04868-22045-2322https://doaj.org/article/36da0b6203544be3912a0cf3797ab0ad2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04868-2https://doaj.org/toc/2045-2322Abstract Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural analysis of vancomycin-Zn(II) crystals and fibre X-ray diffraction. Bioassays indicate that this structure is associated with an increased antibiotic activity against bacterial strains possessing high level vancomycin resistance mediated by the reprogramming of peptidoglycan biosynthesis to use precursors terminating in D-Ala-D-Lac in place of D-Ala-D-Ala. Polymerization occurs via interaction of Zn(II) with the N-terminal methylleucine group of vancomycin, and we show that the activity of other glycopeptide antibiotics with this feature can also be similarly augmented by Zn(II). Construction and analysis of a model strain predominantly using D-Ala-D-Lac precursors for peptidoglycan biosynthesis during normal growth supports the hypothesis that Zn(II) mediated vancomycin polymerization enhances the binding affinity towards these precursors.Ashraf ZarkanHeather-Rose MacklyneDimitri Y. ChirgadzeAndrew D. BondAndrew R. HeskethHee-Jeon HongNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ashraf Zarkan Heather-Rose Macklyne Dimitri Y. Chirgadze Andrew D. Bond Andrew R. Hesketh Hee-Jeon Hong Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
description	Abstract Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural analysis of vancomycin-Zn(II) crystals and fibre X-ray diffraction. Bioassays indicate that this structure is associated with an increased antibiotic activity against bacterial strains possessing high level vancomycin resistance mediated by the reprogramming of peptidoglycan biosynthesis to use precursors terminating in D-Ala-D-Lac in place of D-Ala-D-Ala. Polymerization occurs via interaction of Zn(II) with the N-terminal methylleucine group of vancomycin, and we show that the activity of other glycopeptide antibiotics with this feature can also be similarly augmented by Zn(II). Construction and analysis of a model strain predominantly using D-Ala-D-Lac precursors for peptidoglycan biosynthesis during normal growth supports the hypothesis that Zn(II) mediated vancomycin polymerization enhances the binding affinity towards these precursors.
format	article
author	Ashraf Zarkan Heather-Rose Macklyne Dimitri Y. Chirgadze Andrew D. Bond Andrew R. Hesketh Hee-Jeon Hong
author_facet	Ashraf Zarkan Heather-Rose Macklyne Dimitri Y. Chirgadze Andrew D. Bond Andrew R. Hesketh Hee-Jeon Hong
author_sort	Ashraf Zarkan
title	Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
title_short	Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
title_full	Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
title_fullStr	Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
title_full_unstemmed	Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
title_sort	zn(ii) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/36da0b6203544be3912a0cf3797ab0ad
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_version_	1718394326825828352

Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria

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