7OVH

Crystal structure of the VIM-2 acquired metallo-beta-Lactamase in Complex with compound 14 (JMV-6931)

Summary for 7OVH

• Entry DOI: 10.2210/pdb7ovh/pdb
• Related: 7OVE 7OVF
• Descriptor: Metallo-beta-lactamase VIM-2-like protein, ZINC ION, ACETATE ION, ... (5 entities in total)
• Functional Keywords: metallo-beta-lactamase, vim-2, triazole-thione, inhibitor, zinc, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 1
• Total formula weight: 25853.64

Authors

Tassone, G.,Benvenuti, M.,Verdirosa, F.,Sannio, F.,Marcoccia, F.,Docquier, J.D.,Pozzi, C.,Mangani, S. (deposition date: 2021-06-14, release date: 2021-10-20, Last modification date: 2024-01-31)

Primary citation

Legru, A.,Verdirosa, F.,Hernandez, J.F.,Tassone, G.,Sannio, F.,Benvenuti, M.,Conde, P.A.,Bossis, G.,Thomas, C.A.,Crowder, M.W.,Dillenberger, M.,Becker, K.,Pozzi, C.,Mangani, S.,Docquier, J.D.,Gavara, L.
1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-beta-lactamase inhibitors with re-sensitization activity.
Eur.J.Med.Chem., 226:113873-113873, 2021

PubMed Abstract: Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5. Here, we present a new series of compounds substituted at the 4-position by a thioether-containing alkyl chain with a carboxylic and/or an aryl group at its extremity. Several compounds showed broad-spectrum inhibition with K values in the μM to sub-μM range against VIM-type enzymes, NDM-1 and IMP-1. The presence of the sulfur and of the aryl group was important for the inhibitory activity and the binding mode of a few compounds in VIM-2 was revealed by X-ray crystallography. Importantly, in vitro antibacterial susceptibility assays showed that several inhibitors were able to potentiate the activity of meropenem on Klebsiella pneumoniae clinical isolates producing VIM-1 or VIM-4, with a potentiation effect of up to 16-fold. Finally, a selected compound was found to only moderately inhibit the di-zinc human glyoxalase II, and several showed no or only moderate toxicity toward several human cells, thus favourably completing a promising behaviour.

PubMed: 34626878
DOI: 10.1016/j.ejmech.2021.113873

Experimental method

X-RAY DIFFRACTION (1.8 Å)