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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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