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Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates
β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979060/ https://www.ncbi.nlm.nih.gov/pubmed/27499424 http://dx.doi.org/10.1038/ncomms12406 |
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author | Brem, Jürgen Cain, Ricky Cahill, Samuel McDonough, Michael A. Clifton, Ian J. Jiménez-Castellanos, Juan-Carlos Avison, Matthew B. Spencer, James Fishwick, Colin W. G. Schofield, Christopher J. |
author_facet | Brem, Jürgen Cain, Ricky Cahill, Samuel McDonough, Michael A. Clifton, Ian J. Jiménez-Castellanos, Juan-Carlos Avison, Matthew B. Spencer, James Fishwick, Colin W. G. Schofield, Christopher J. |
author_sort | Brem, Jürgen |
collection | PubMed |
description | β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. |
format | Online Article Text |
id | pubmed-4979060 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49790602016-08-23 Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates Brem, Jürgen Cain, Ricky Cahill, Samuel McDonough, Michael A. Clifton, Ian J. Jiménez-Castellanos, Juan-Carlos Avison, Matthew B. Spencer, James Fishwick, Colin W. G. Schofield, Christopher J. Nat Commun Article β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. Nature Publishing Group 2016-08-08 /pmc/articles/PMC4979060/ /pubmed/27499424 http://dx.doi.org/10.1038/ncomms12406 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Brem, Jürgen Cain, Ricky Cahill, Samuel McDonough, Michael A. Clifton, Ian J. Jiménez-Castellanos, Juan-Carlos Avison, Matthew B. Spencer, James Fishwick, Colin W. G. Schofield, Christopher J. Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
title | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
title_full | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
title_fullStr | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
title_full_unstemmed | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
title_short | Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
title_sort | structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979060/ https://www.ncbi.nlm.nih.gov/pubmed/27499424 http://dx.doi.org/10.1038/ncomms12406 |
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