4-( N -Alkyl- and -Acyl-amino)-1,2,4-triazole-3-thione Analogs as Metallo-β-Lactamase Inhibitors: Impact of 4-Linker on Potency and Spectrum of Inhibition

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 8; p. 1094
• Main Authors: Gavara, Laurent, Verdirosa, Federica, Legru, Alice, Mercuri, Paola Sandra, Nauton, Lionel, Sevaille, Laurent, Feller, Georges, Berthomieu, Dorothée, Sannio, Filomena, Marcoccia, Francesca, Tanfoni, Silvia, De Luca, Filomena, Gresh, Nohad, Galleni, Moreno, Docquier, Jean-Denis, Hernandez, Jean-François
• Format: Journal Article Web Resource
• Language: English
• Published: Switzerland MDPI AG 23.07.2020; MDPI; Multidisciplinary Digital Publishing Institute (MDPI)
• Subjects: 1,2,4-triazole-3-thione; Anti-Bacterial Agents; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Bacterial Infections; Bacterial Infections - microbiology; Bacterial Infections - prevention & control; bacterial resistance; Beta-Lactamase Inhibitors; beta-Lactamase Inhibitors - chemistry; beta-Lactamase Inhibitors - pharmacology; Beta-Lactamases; beta-Lactamases - metabolism; Beta-Lactams; beta-Lactams - chemistry; beta-Lactams - pharmacology; Biocatalysis; Biocatalysis - drug effects; Biochemistry, biophysics & molecular biology; Biochimie, biophysique & biologie moléculaire; Calorimetry; Carbapenems; Carbapenems - chemistry; Carbapenems - pharmacology; Chemical Sciences; Drug development; Drug resistance; Drug Resistance, Bacterial; Drug Resistance, Bacterial - drug effects; enzyme inhibitors; Enzymes; Gram-Negative Bacteria; Gram-Negative Bacteria - drug effects; Gram-Negative Bacteria - metabolism; Humans; Hydrazine; Infections; Life sciences; Medicinal Chemistry; Metallo-β-lactamase; Microbial Sensitivity Tests; Microbiologie; Microbiology; Molecular Structure; Pathogens; Physicochemical properties; Sciences du vivant; Thiones; Thiones - chemistry; Titration; Triazoles; Triazoles - chemistry; Zinc; β-Lactam antibiotics; β-lactam antibiotics; 1,2,4-triazole-3-thione; enzyme inhibitors; metallo-β-lactamase; bacterial resistance; 4-triazole-3-thione; 1; Metallo-β-lactamase; 2; Enzyme inhibitors; Bacterial resistance
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10081094

To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-β-lactamases (MBLs), which represent major resistance determinants to β-lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series); the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with values in the micromolar to submicromolar range. One of these showed broad-spectrum inhibition as it also significantly inhibited VIM-1 and NDM-1. Restoration of β-lactam activity in microbiological assays was observed for one selected compound. Finally, the binding to the VIM-2 active site was evaluated by isothermal titration calorimetry and a modeling study explored the effect of the linker structure on the mode of binding with this MBL.