1. Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates
- Author
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Alice Legru, Federica Verdirosa, Yen Vo-Hoang, Giusy Tassone, Filippo Vascon, Caitlyn A. Thomas, Filomena Sannio, Giuseppina Corsica, Manuela Benvenuti, Georges Feller, Rémi Coulon, Francesca Marcoccia, Savannah Rowane Devente, Ezeddine Bouajila, Catherine Piveteau, Florence Leroux, Rebecca Deprez-Poulain, Benoît Deprez, Patricia Licznar-Fajardo, Michael W. Crowder, Laura Cendron, Cecilia Pozzi, Stefano Mangani, Jean-Denis Docquier, Jean-François Hernandez, Laurent Gavara, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM), Università degli Studi di Siena = University of Siena (UNISI), Università degli Studi di Padova = University of Padua (Unipd), Miami University [Ohio] (MU), Université de Liège, Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Hydrosciences Montpellier (HSM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) more...
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MESH: Microbial Sensitivity Tests ,MESH: Humans ,Inhibitors ,[SDV]Life Sciences [q-bio] ,MESH: beta-Lactamases ,Thiones ,Microbial Sensitivity Tests ,Metallo β-lactamase ,beta-Lactamases ,Anti-Bacterial Agents ,Triazole-thione ,Antibiotics ,MESH: Anti-Bacterial Agents ,Carbapenem resistant enterobacteriaceae ,MESH: HeLa Cells ,Drug Discovery ,[CHIM]Chemical Sciences ,Molecular Medicine ,Humans ,MESH: Thiones ,beta-Lactamase Inhibitors ,MESH: beta-Lactamase Inhibitors ,HeLa Cells - Abstract
International audience; 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 (Ki = 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. more...
- Published
- 2022
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