[en] Metallo-β-lactamases (MBLs) represent an increasingly serious threat to public health because of their increased prevalence worldwide in relevant opportunistic Gram-negative pathogens. MBLs efficiently inactivate widely used and most valuable β-lactam antibiotics, such as oxyiminocephalosporins (ceftriaxone, ceftazidime) and the last-resort carbapenems. To date, no MBL inhibitor has been approved for therapeutic applications. We are developing inhibitors characterized by a 1,2,4-triazole-3-thione scaffold as an original zinc ligand and few promising series were already reported. Here, we present the synthesis and evaluation of a new series of compounds characterized by the presence of an arylalkyl substituent at position 4 of the triazole ring. The alkyl link was mainly an ethylene, but a few compounds without alkyl or with an alkyl group of various lengths up to a butyl chain were also synthesized. Some compounds in both sub-series were micromolar to submicromolar inhibitors of tested VIM-type MBLs. A few of them were broad-spectrum inhibitors, as they showed significant inhibitory activity on NDM-1 and, to a lesser extent, IMP-1. Among these, several inhibitors were able to significantly reduce the meropenem MIC on VIM-1- and VIM-4- producing clinical isolates by up to 16-fold. In addition, ACE inhibition was absent or moderate and one promising compound did not show toxicity toward HeLa cells at concentrations up to 250 μM. This series represents a promising basis for further exploration. Finally, molecular modelling of representative compounds in complex with VIM-2 was performed to study their binding mode.
Disciplines :
Microbiology Biochemistry, biophysics & molecular biology Life sciences: Multidisciplinary, general & others
Author, co-author :
Gavara, Laurent; Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France. Electronic address: laurent.gavara@umontpellier.fr
Verdirosa, Federica; Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy
Sevaille, Laurent; Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Legru, Alice; Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Corsica, Giuseppina; Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy
Nauton, Lionel; Institut de Chimie de Clermont-Ferrand, Université Clermont-Auvergne, CNRS, Clermont-Ferrand, France
Mercuri, Paola ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Sannio, Filomena; Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy
De Luca, Filomena; Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy
Hadjadj, Margot; Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Cerboni, Giulia; Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy
Vo Hoang, Yen; Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, Montpellier, France
Licznar-Fajardo, Patricia; HSM, Univ Montpellier, CNRS, IRD, CHU Montpellier, France
Galleni, Moreno ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Part of this work was supported by Agence Nationale de la Recherche (ANR-14-CE16-0028-01, including fellowship to L.S.). We thank Mr Pierre Sanchez for mass spectrometry analyses.
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