Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2019
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| _version_ | 1826299708313698304 |
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| author | Krajnc, A Brem, J Hinchliffe, P Calvopiña, K Panduwawala, TD Lang, PA Kamps, JJAG Tyrrell, JM Widlake, E Saward, BG Walsh, TR Spencer, J Schofield, CJ |
| author_facet | Krajnc, A Brem, J Hinchliffe, P Calvopiña, K Panduwawala, TD Lang, PA Kamps, JJAG Tyrrell, JM Widlake, E Saward, BG Walsh, TR Spencer, J Schofield, CJ |
| author_sort | Krajnc, A |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T05:06:04Z |
| format | Journal article |
| id | oxford-uuid:d9f61593-1703-4036-b80d-aac2bffd8173 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:06:04Z |
| publishDate | 2019 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:d9f61593-1703-4036-b80d-aac2bffd81732022-03-27T08:59:47ZBicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamasesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d9f61593-1703-4036-b80d-aac2bffd8173EnglishSymplectic Elements at OxfordAmerican Chemical Society2019Krajnc, ABrem, JHinchliffe, PCalvopiña, KPanduwawala, TDLang, PAKamps, JJAGTyrrell, JMWidlake, ESaward, BGWalsh, TRSpencer, JSchofield, CJThe 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. |
| spellingShingle | Krajnc, A Brem, J Hinchliffe, P Calvopiña, K Panduwawala, TD Lang, PA Kamps, JJAG Tyrrell, JM Widlake, E Saward, BG Walsh, TR Spencer, J Schofield, CJ Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases |
| title | 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_short | Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases |
| title_sort | bicyclic boronate vnrx 5133 inhibits metallo and serine β lactamases |
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