6RMF

Crystal structure of NDM-1 with VNRX-5133

Summary for 6RMF

• Entry DOI: 10.2210/pdb6rmf/pdb
• Descriptor: Metallo-beta-lactamase type 2, ZINC ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: metallo-beta-lactamase, antibiotic resistance, inhibitor, antimicrobial protein
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 53284.48

Authors

Hinchliffe, P.,Spencer, J.,Brem, J.,Schofield, C.J. (deposition date: 2019-05-06, release date: 2019-09-11, Last modification date: 2024-01-24)

Primary citation

Krajnc, A.,Brem, J.,Hinchliffe, P.,Calvopina, K.,Panduwawala, T.D.,Lang, P.A.,Kamps, J.J.A.G.,Tyrrell, J.M.,Widlake, E.,Saward, B.G.,Walsh, T.R.,Spencer, J.,Schofield, C.J.
Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-beta-Lactamases.
J.Med.Chem., 62:8544-8556, 2019

PubMed 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 (sp) 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.

PubMed: 31454231
DOI: 10.1021/acs.jmedchem.9b00911

Experimental method

X-RAY DIFFRACTION (1.51 Å)