Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases

Krajnc, Alen; Brem, Jürgen; Hinchliffe, Philip; Calvopiña, Karina; Panduwawala, Tharindi D.; Lang, Pauline A.; A., Jos J.; Tyrrell, Jon; Widlake, Emma; Saward, Benjamin G.; Walsh, Timothy R.; Spencer, James; Schofield, Christopher J.

doi:10.1021/acs.jmedchem.9b00911

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Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases

Alen Krajnc

, Jürgen Brem

, Philip Hinchliffe

, Karina Calvopiña, Tharindi D. Panduwawala, Pauline A. Lang

, Jos J. A. G. Kamps, Jon Tyrrell

, Emma Widlake, Benjamin G. Saward, Timothy R. Walsh, James Spencer

, Christopher J. Schofield

Journal of Medicinal Chemistry, Volume: 62, Issue: 18, Pages: 8544 - 8556

Swansea University Author: Jon Tyrrell

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DOI (Published version): 10.1021/acs.jmedchem.9b00911

Abstract

The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and te...

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Published in:	Journal of Medicinal Chemistry
ISSN:	0022-2623 1520-4804
Published:	American Chemical Society (ACS) 2019
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa70432

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last_indexed	2025-10-17T09:30:56Z
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The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. 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spelling	2025-10-16T13:36:54.2347512 v2 70432 2025-09-21 Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases ad510c73555adf718387af219e235a6e 0000-0001-8565-2590 Jon Tyrrell Jon Tyrrell true false 2025-09-21 MEDS The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the “high-energy-intermediate” analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes. Journal Article Journal of Medicinal Chemistry 62 18 8544 8556 American Chemical Society (ACS) 0022-2623 1520-4804 26 9 2019 2019-09-26 10.1021/acs.jmedchem.9b00911 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee thank the Wellcome Trust, Cancer Research U.K., the Medical Research Council, the Biotechnology and Biological Research Council (BB/S50676X/1), the Innovative Medicines Initiative (European Lead factory and ENABLE components), for funding our work on antibiotics, MBL fold enzymes, and β-lactamase inhibitors. The work was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant R01AI100560 (J.S). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work has been facilitated by the BrisSynBio Biosuite (U.K. Biotechnology and Biological Sciences (BBSRC) and Engineering and Physical Sciences (EPSRC) Research Councils, BB/L01386X/1) and the BBSRC ALERT14 equipment initiative (BB/M012107/1). 2025-10-16T13:36:54.2347512 2025-09-21T18:15:47.5081807 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Alen Krajnc 0000-0001-7822-1944 1 Jürgen Brem 0000-0002-0137-3226 2 Philip Hinchliffe 0000-0001-8611-4743 3 Karina Calvopiña 4 Tharindi D. Panduwawala 5 Pauline A. Lang 0000-0003-3187-1469 6 Jos J. A. G. Kamps 7 Jon Tyrrell 0000-0001-8565-2590 8 Emma Widlake 9 Benjamin G. Saward 10 Timothy R. Walsh 11 James Spencer 0000-0002-4602-0571 12 Christopher J. Schofield 0000-0002-0290-6565 13 70432__35364__780ee66e450547db9c4fab8068178212.pdf 70432.VoR.pdf 2025-10-16T13:30:16.9001608 Output 3957520 application/pdf Version of Record true © 2019 American Chemical Society. This publication is licensed under CC-BY license. true eng https://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html
title	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
spellingShingle	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases Jon Tyrrell
title_short	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
title_full	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
title_fullStr	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
title_full_unstemmed	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
title_sort	Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
author_id_str_mv	ad510c73555adf718387af219e235a6e
author_id_fullname_str_mv	ad510c73555adf718387af219e235a6e_***_Jon Tyrrell
author	Jon Tyrrell
author2	Alen Krajnc Jürgen Brem Philip Hinchliffe Karina Calvopiña Tharindi D. Panduwawala Pauline A. Lang Jos J. A. G. Kamps Jon Tyrrell Emma Widlake Benjamin G. Saward Timothy R. Walsh James Spencer Christopher J. Schofield
format	Journal article
container_title	Journal of Medicinal Chemistry
container_volume	62
container_issue	18
container_start_page	8544
publishDate	2019
institution	Swansea University
issn	0022-2623 1520-4804
doi_str_mv	10.1021/acs.jmedchem.9b00911
publisher	American Chemical Society (ACS)
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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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
document_store_str	1
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description	The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the “high-energy-intermediate” analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.
published_date	2019-09-26T05:30:52Z
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score	11.089386

Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases

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