8a4m | pdb_00008a4m

Crystal structure of the VIM-2 acquired metallo-beta-Lactamase in complex with compound 8 (JMV-7061)

spinqualitylabelsall models 8a4m, resolution 1.98Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8a4m 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. Ligands: ACT, L2R, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function B8QIQ9_PSEAI Publication Abstract from PubMed Metallo-beta-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an alpha-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition (K(i) = 10-30 nM). Equilibrium dialysis, native mass spectrometry, isothermal calorimetry (ITC), and X-ray crystallography showed that the compounds inhibited both VIM-2 and NDM-1 at least partially by stripping the catalytic zinc ions. These inhibitors also displayed a very potent synergistic activity with meropenem (16- to 1000-fold minimum inhibitory concentration (MIC) reduction) against VIM-type- and NDM-1-producing ultraresistant clinical isolates, including Enterobacterales and Pseudomonas aeruginosa. Furthermore, selected compounds exhibited no or moderate toxicity toward HeLa cells, favorable absorption, distribution, metabolism, excretion (ADME) properties, and no or modest inhibition of several mammalian metalloenzymes. Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-beta-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates.,Legru A, Verdirosa F, Vo-Hoang Y, Tassone G, Vascon F, Thomas CA, Sannio F, Corsica G, Benvenuti M, Feller G, Coulon R, Marcoccia F, Devente SR, Bouajila E, Piveteau C, Leroux F, Deprez-Poulain R, Deprez B, Licznar-Fajardo P, Crowder MW, Cendron L, Pozzi C, Mangani S, Docquier JD, Hernandez JF, Gavara L J Med Chem. 2022 Nov 30. doi: 10.1021/acs.jmedchem.2c01257. PMID:36450011 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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