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Open AccessArticle

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

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Institut des Biomolécules Max Mousseron, UMR5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 34093 Montpellier, France
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Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy
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Laboratoire des Macromolécules Biologiques, Centre d’Ingénierie des Protéines-InBioS, Université de Liège, Institute of Chemistry B6 a, Sart-Tilman, 4000 Liège, Belgium
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Institut de Chimie de Clermont-Ferrand, Université Clermont-Auvergne, CNRS, SIGMA Clermont, 63000 Clermont-Ferrand, France
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Laboratoire de Biochimie, Centre d’Ingénierie des Protéines-InBioS, Université de Liège, B6, Sart-Tilman, 4000 Liège, Belgium
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Institut Charles Gerhardt, UMR5253, CNRS, Université de Montpellier, ENSCM, Cedex 5, 34296 Montpellier, France
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Laboratoire de Chimie Théorique, UMR7616, Sorbonne Université, CNRS, 75252 Paris, France
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(8), 1094; https://doi.org/10.3390/biom10081094
Received: 15 June 2020 / Revised: 17 July 2020 / Accepted: 19 July 2020 / Published: 23 July 2020
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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 Ki 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. View Full-Text
Keywords: metallo-β-lactamase; 1,2,4-triazole-3-thione; bacterial resistance; β-lactam antibiotics; enzyme inhibitors metallo-β-lactamase; 1,2,4-triazole-3-thione; bacterial resistance; β-lactam antibiotics; enzyme inhibitors
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Gavara, L.; Verdirosa, F.; Legru, A.; Mercuri, P.S.; Nauton, L.; Sevaille, L.; Feller, G.; Berthomieu, D.; Sannio, F.; Marcoccia, F.; Tanfoni, S.; De Luca, F.; Gresh, N.; Galleni, M.; Docquier, J.-D.; Hernandez, J.-F. 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. Biomolecules 2020, 10, 1094.

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