8A4M

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

Summary for 8A4M

• Entry DOI: 10.2210/pdb8a4m/pdb
• 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: 26306.17

Authors

Tassone, G.,Benvenuti, M.,Verdirosa, F.,Corsica, G.,Sannio, F.,Docquier, J.D.,Pozzi, C.,Mangani, S. (deposition date: 2022-06-13, release date: 2023-04-26, Last modification date: 2024-02-07)

Primary citation

Legru, A.,Verdirosa, F.,Vo-Hoang, Y.,Tassone, G.,Vascon, F.,Thomas, C.A.,Sannio, F.,Corsica, G.,Benvenuti, M.,Feller, G.,Coulon, R.,Marcoccia, F.,Devente, S.R.,Bouajila, E.,Piveteau, C.,Leroux, F.,Deprez-Poulain, R.,Deprez, B.,Licznar-Fajardo, P.,Crowder, M.W.,Cendron, L.,Pozzi, C.,Mangani, S.,Docquier, J.D.,Hernandez, J.F.,Gavara, L.
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.
J.Med.Chem., 65:16392-16419, 2022

PubMed Abstract: Metallo-β-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 α-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 ( = 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 and . 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.

PubMed: 36450011
DOI: 10.1021/acs.jmedchem.2c01257

Experimental method

X-RAY DIFFRACTION (1.98 Å)