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
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Publicado: Nature Portfolio 2017
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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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