8A76

Metallo-beta-lactamase NDM-1 in complex with 1,2,4-Triazole-3-thione compound 26

Summary for 8A76

• Entry DOI: 10.2210/pdb8a76/pdb
• Descriptor: Metallo-beta-lactamase NDM-1, ZINC ION, CALCIUM ION, ... (8 entities in total)
• Functional Keywords: metallo-beta-lactamase, hydrolase
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 53111.23

Authors

Vascon, F.,Legru, A.,Hernandez, J.F.,Cendron, L. (deposition date: 2022-06-20, release date: 2022-12-14, Last modification date: 2024-01-31)

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 (1.5 Å)