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.

Autor: Legru A; IBMM, CNRS, Univ Montpellier, ENSCM, Montpellier, France., Verdirosa F; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy., Hernandez JF; IBMM, CNRS, Univ Montpellier, ENSCM, Montpellier, France. Electronic address: jean-francois.hernandez@umontpellier.fr., Tassone G; Dipartimento di Biotecnologie, Chimica e Pharmacia, Università di Siena, 53100, Siena, Italy., Sannio F; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy., Benvenuti M; Dipartimento di Biotecnologie, Chimica e Pharmacia, Università di Siena, 53100, Siena, Italy., Conde PA; IBMM, CNRS, Univ Montpellier, ENSCM, Montpellier, France., Bossis G; IGMM, Univ Montpellier, CNRS, Montpellier, France., Thomas CA; Department of Chemistry and Biochemistry, Miami University, Oxford, OH, USA., Crowder MW; Department of Chemistry and Biochemistry, Miami University, Oxford, OH, USA., Dillenberger M; Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, D-35392, Giessen, Germany., Becker K; Chair of Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, D-35392, Giessen, Germany., Pozzi C; Dipartimento di Biotecnologie, Chimica e Pharmacia, Università di Siena, 53100, Siena, Italy., Mangani S; Dipartimento di Biotecnologie, Chimica e Pharmacia, Università di Siena, 53100, Siena, Italy., Docquier JD; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100, Siena, Italy; Centre d'Ingénierie des Protéines-InBioS, Université de Liège, B-4000, Liège, Belgium. Electronic address: jddocquier@unisi.it., Gavara L; IBMM, CNRS, Univ Montpellier, ENSCM, Montpellier, France. Electronic address: laurent.gavara@umontpellier.fr.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Dec 15; Vol. 226, pp. 113873. Date of Electronic Publication: 2021 Oct 04.
DOI: 10.1016/j.ejmech.2021.113873
Abstrakt: 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 K i 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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