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Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
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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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© 2019 American Chemical Society. This publication is licensed under CC-BY license.
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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...
| Published in: | Journal of Medicinal Chemistry |
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| ISSN: | 0022-2623 1520-4804 |
| Published: |
American Chemical Society (ACS)
2019
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70432 |
| 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 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. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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). |
| Issue: |
18 |
| Start Page: |
8544 |
| End Page: |
8556 |