7ovh

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

spinqualitylabelsall models 7ovh, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ovh is a 1 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: ACT, UNL, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9K2N0_PSEAI Publication Abstract from PubMed Metallo-beta-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to beta-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 Ki values in the muM to sub-muM 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. 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.,Legru A, Verdirosa F, Hernandez JF, Tassone G, Sannio F, Benvenuti M, Conde PA, Bossis G, Thomas CA, Crowder MW, Dillenberger M, Becker K, Pozzi C, Mangani S, Docquier JD, Gavara L Eur J Med Chem. 2021 Oct 4;226:113873. doi: 10.1016/j.ejmech.2021.113873. PMID:34626878 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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