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Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli
Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate t...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356297/ https://www.ncbi.nlm.nih.gov/pubmed/32545682 http://dx.doi.org/10.3390/biom10060899 |
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author | Lang, Pauline A. Parkova, Anete Leissing, Thomas M. Calvopiña, Karina Cain, Ricky Krajnc, Alen Panduwawala, Tharindi D. Philippe, Jules Fishwick, Colin W. G. Trapencieris, Peteris Page, Malcolm G. P. Schofield, Christopher J. Brem, Jürgen |
author_facet | Lang, Pauline A. Parkova, Anete Leissing, Thomas M. Calvopiña, Karina Cain, Ricky Krajnc, Alen Panduwawala, Tharindi D. Philippe, Jules Fishwick, Colin W. G. Trapencieris, Peteris Page, Malcolm G. P. Schofield, Christopher J. Brem, Jürgen |
author_sort | Lang, Pauline A. |
collection | PubMed |
description | Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition. |
format | Online Article Text |
id | pubmed-7356297 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73562972020-07-31 Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli Lang, Pauline A. Parkova, Anete Leissing, Thomas M. Calvopiña, Karina Cain, Ricky Krajnc, Alen Panduwawala, Tharindi D. Philippe, Jules Fishwick, Colin W. G. Trapencieris, Peteris Page, Malcolm G. P. Schofield, Christopher J. Brem, Jürgen Biomolecules Article Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β-lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β-lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition. MDPI 2020-06-12 /pmc/articles/PMC7356297/ /pubmed/32545682 http://dx.doi.org/10.3390/biom10060899 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lang, Pauline A. Parkova, Anete Leissing, Thomas M. Calvopiña, Karina Cain, Ricky Krajnc, Alen Panduwawala, Tharindi D. Philippe, Jules Fishwick, Colin W. G. Trapencieris, Peteris Page, Malcolm G. P. Schofield, Christopher J. Brem, Jürgen Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli |
title | Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli |
title_full | Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli |
title_fullStr | Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli |
title_full_unstemmed | Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli |
title_short | Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli |
title_sort | bicyclic boronates as potent inhibitors of ampc, the class c β-lactamase from escherichia coli |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356297/ https://www.ncbi.nlm.nih.gov/pubmed/32545682 http://dx.doi.org/10.3390/biom10060899 |
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