Profiling interactions of vaborbactam with metallo-β-lactamases

Langley, Gareth W.; Cain, Ricky; Tyrrell, Jon; Hinchliffe, Philip; Calvopiña, Karina; Tooke, Catherine L.; Widlake, Emma; Dowson, Christopher G.; Spencer, James; Walsh, Timothy R.; Schofield, Christopher J.; Brem, Jürgen

doi:10.1016/j.bmcl.2019.05.031

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Profiling interactions of vaborbactam with metallo-β-lactamases

Gareth W. Langley, Ricky Cain

, Jon Tyrrell

, Philip Hinchliffe, Karina Calvopiña, Catherine L. Tooke, Emma Widlake, Christopher G. Dowson, James Spencer, Timothy R. Walsh, Christopher J. Schofield

, Jürgen Brem

Bioorganic & Medicinal Chemistry Letters, Volume: 29, Issue: 15, Pages: 1981 - 1984

Swansea University Author: Jon Tyrrell

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DOI (Published version): 10.1016/j.bmcl.2019.05.031

Abstract

β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that utilise a zinc-bo...

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Published in:	Bioorganic & Medicinal Chemistry Letters
ISSN:	0960-894X
Published:	Elsevier BV 2019
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa70434

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Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-β-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20–100 fold below that by which it inhibits its current clinical targets, the Class A serine β-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which presently lack activity against B2 and B3 enzymes. 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spelling	2025-10-13T16:06:14.0746945 v2 70434 2025-09-21 Profiling interactions of vaborbactam with metallo-β-lactamases ad510c73555adf718387af219e235a6e 0000-0001-8565-2590 Jon Tyrrell Jon Tyrrell true false 2025-09-21 MEDS β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that utilise a zinc-bound water nucleophile. Achieving simultaneous inhibition of both β-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-β-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20–100 fold below that by which it inhibits its current clinical targets, the Class A serine β-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which presently lack activity against B2 and B3 enzymes. These findings indicate that cyclic boronate scaffolds have the potential to inhibit the full range of β-lactamases and justify further work on the development of boronates as broad-spectrum β-lactamase inhibitors. Journal Article Bioorganic & Medicinal Chemistry Letters 29 15 1981 1984 Elsevier BV 0960-894X Vaborbactam; Serine- and metallo-β-lactamase; Transition state analogue; Boronate inhibitor; β-Lactamase induction; Antibiotic resistance 1 8 2019 2019-08-01 10.1016/j.bmcl.2019.05.031 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee We thank the Wellcome Trust, Cancer Research UK, the Medical Research Council, the SWON alliance (MR/N002679/1), the Biotechnology and Biological Research Council (BB/S50676X/1)BB/S50676X/1, and the Innovative Medicines Initiative (European Lead factory and ENABLE components), for funding our work on antibiotics, MBL fold enzymes, and β-lactamase inhibitors. 2025-10-13T16:06:14.0746945 2025-09-21T18:16:29.8055241 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Gareth W. Langley 1 Ricky Cain 0000-0001-5272-7760 2 Jon Tyrrell 0000-0001-8565-2590 3 Philip Hinchliffe 4 Karina Calvopiña 5 Catherine L. Tooke 6 Emma Widlake 7 Christopher G. Dowson 8 James Spencer 9 Timothy R. Walsh 10 Christopher J. Schofield 0000-0002-0290-6565 11 Jürgen Brem 0000-0002-0137-3226 12 70434__35328__5817a0dee7664225b95c6dcabdc887db.pdf 70434.VoR.pdf 2025-10-13T15:55:06.2385140 Output 1894626 application/pdf Version of Record true © 2019 The Authors. This is an open access article under the CC BY license. true eng https://doi.org/10.1016/j.bmcl.2019.05.031
title	Profiling interactions of vaborbactam with metallo-β-lactamases
spellingShingle	Profiling interactions of vaborbactam with metallo-β-lactamases Jon Tyrrell
title_short	Profiling interactions of vaborbactam with metallo-β-lactamases
title_full	Profiling interactions of vaborbactam with metallo-β-lactamases
title_fullStr	Profiling interactions of vaborbactam with metallo-β-lactamases
title_full_unstemmed	Profiling interactions of vaborbactam with metallo-β-lactamases
title_sort	Profiling interactions of vaborbactam with metallo-β-lactamases
author_id_str_mv	ad510c73555adf718387af219e235a6e
author_id_fullname_str_mv	ad510c73555adf718387af219e235a6e_***_Jon Tyrrell
author	Jon Tyrrell
author2	Gareth W. Langley Ricky Cain Jon Tyrrell Philip Hinchliffe Karina Calvopiña Catherine L. Tooke Emma Widlake Christopher G. Dowson James Spencer Timothy R. Walsh Christopher J. Schofield Jürgen Brem
format	Journal article
container_title	Bioorganic & Medicinal Chemistry Letters
container_volume	29
container_issue	15
container_start_page	1981
publishDate	2019
institution	Swansea University
issn	0960-894X
doi_str_mv	10.1016/j.bmcl.2019.05.031
publisher	Elsevier BV
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that utilise a zinc-bound water nucleophile. Achieving simultaneous inhibition of both β-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-β-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20–100 fold below that by which it inhibits its current clinical targets, the Class A serine β-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which presently lack activity against B2 and B3 enzymes. These findings indicate that cyclic boronate scaffolds have the potential to inhibit the full range of β-lactamases and justify further work on the development of boronates as broad-spectrum β-lactamase inhibitors.
published_date	2019-08-01T05:30:52Z
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Profiling interactions of vaborbactam with metallo-β-lactamases

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