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1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity

DOI: 10.1016/j.ejmech.2021.113873 DOI Help

Authors: Alice Legru (IBMM, CNRS, Univ Montpellier) , Federica Verdirosa (Università di Siena) , Jean-François Hernandez (IBMM, CNRS, Univ Montpellier) , Giusi Tassone (Università di Siena) , Filomena Sannio (Università di Siena) , Manuela Benvenuti (Università di Siena) , Pierre-Alexis Conde (IBMM, CNRS, Univ Montpellier) , Guillaume Bossis (IGMM, Univ Montpellier, CNRS) , Caitlyn A. Thomas (Miami University) , Michael W. Crowder (Miami University) , Melissa Dillenberger (Justus Liebig University) , Katja Becker (Justus Liebig University) , Cecilia Pozzi (Università di Siena) , Stefano Mangani (Università di Siena) , Jean-Denis Docquier (Università di Siena; Université de Liège) , Laurent Gavara (BMM, CNRS, Univ Montpellier)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 40

State: Published (Approved)
Published: October 2021
Diamond Proposal Number(s): 21741

Abstract: Metallo-β-lactamases (MBLs) are important contributors of Gram-negative bacteria resistance to β-lactam antibiotics. MBLs are highly worrying because of their carbapenemase activity, their rapid spread in major human opportunistic pathogens while no clinically useful inhibitor is available yet. In this context, we are exploring the potential of compounds based on the 1,2,4-triazole-3-thione scaffold as an original ligand of the di-zinc active sites of MBLs, and diversely substituted at its positions 4 and 5. Here, we present a new series of compounds substituted at the 4-position by a thioether-containing alkyl chain with a carboxylic and/or an aryl group at its extremity. Several compounds showed broad-spectrum inhibition with Ki values in the μM to sub-μM range against VIM-type enzymes, NDM-1 and IMP-1. The presence of the sulfur and of the aryl group was important for the inhibitory activity and the binding mode of a few compounds in VIM-2 was revealed by X-ray crystallography. Importantly, in vitro antibacterial susceptibility assays showed that several inhibitors were able to potentiate the activity of meropenem on Klebsiella pneumoniae clinical isolates producing VIM-1 or VIM-4, with a potentiation effect of up to 16-fold. Finally, a selected compound was found to only moderately inhibit the di-zinc human glyoxalase II, and several showed no or only moderate toxicity toward several human cells, thus favourably completing a promising behaviour.

Journal Keywords: Metallo-β-Lactamase inhibitor; 1,2,4-Triazole-3-thione; Bacterial resistance; β-lactam antibiotic; Thioether

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 06/10/2021 08:57

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)