6F2N

Crystal structure of BCII Metallo-beta-lactamase in complex with KDU197

Summary for 6F2N

• Entry DOI: 10.2210/pdb6f2n/pdb
• Related: 5JMX 6EUM 6EW3 6EWE
• Descriptor: Metallo-beta-lactamase type 2, ZINC ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: antimicrobial resistance, metallo beta lactamase, inhibitor, hydrolase
• Biological source: Bacillus cereus
• Total number of polymer chains: 1
• Total formula weight: 25542.82

Authors

McDonough, M.A.,El-Hussein, A.,Schofield, C.J.,Zhang, D.,Brem, J. (deposition date: 2017-11-24, release date: 2018-10-03, Last modification date: 2024-01-17)

Primary citation

Zhang, D.,Markoulides, M.S.,Stepanovs, D.,Rydzik, A.M.,El-Hussein, A.,Bon, C.,Kamps, J.J.A.G.,Umland, K.D.,Collins, P.M.,Cahill, S.T.,Wang, D.Y.,von Delft, F.,Brem, J.,McDonough, M.A.,Schofield, C.J.
Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-beta-lactamases.
Bioorg. Med. Chem., 26:2928-2936, 2018

PubMed Abstract: Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

PubMed: 29655609
DOI: 10.1016/j.bmc.2018.02.043

Experimental method

X-RAY DIFFRACTION (1.149 Å)