Optimization of 1,2,4-Triazole-3-thiones toward Broad-Spectrum Metallo-β-lactamase Inhibitors Showing Potent Synergistic Activity on VIM- and NDM-1-Producing Clinical Isolates.

Autor: Legru A; IBMM, CNRS, Univ Montpellier, ENSCM, 34000 Montpellier, France., Verdirosa F; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy., Vo-Hoang Y; IBMM, CNRS, Univ Montpellier, ENSCM, 34000 Montpellier, France., Tassone G; Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, 53100 Siena, Italy., Vascon F; Laboratory of Structural Biology, Department of Biology, University of Padua, 35121 Padova, Italy., Thomas CA; Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States., Sannio F; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy., Corsica G; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy., Benvenuti M; Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, 53100 Siena, Italy., Feller G; Laboratoire de Biochimie, Centre d'Ingénierie des Protéines-InBioS, Université de Liège, Allée du 6 août B6, Sart-Tilman, B-4000 Liège, Belgium., Coulon R; IBMM, CNRS, Univ Montpellier, ENSCM, 34000 Montpellier, France., Marcoccia F; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy., Devente SR; Dipartimento di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy., Bouajila E; IBMM, CNRS, Univ Montpellier, ENSCM, 34000 Montpellier, France., Piveteau C; Drugs and Molecules for Living System, U1177, Inserm, Université de Lille, Faculté de Pharmacie, 59006 Lille, France., Leroux F; Drugs and Molecules for Living System, U1177, Inserm, Université de Lille, Faculté de Pharmacie, 59006 Lille, France., Deprez-Poulain R; Drugs and Molecules for Living System, U1177, Inserm, Université de Lille, Faculté de Pharmacie, 59006 Lille, France., Deprez B; Drugs and Molecules for Living System, U1177, Inserm, Université de Lille, Faculté de Pharmacie, 59006 Lille, France., Licznar-Fajardo P; HydroSciences Montpellier, UMR5151, Univ Montpellier, CNRS, IRD, CHU Montpellier, 34000 Montpellier, France., Crowder MW; Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio 45056, United States., Cendron L; Laboratory of Structural Biology, Department of Biology, University of Padua, 35121 Padova, Italy., Pozzi C; Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, 53100 Siena, Italy., Mangani S; Dipartimento di Biotecnologie, Chimica e Farmacia, 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., Hernandez JF; IBMM, CNRS, Univ Montpellier, ENSCM, 34000 Montpellier, France., Gavara L; IBMM, CNRS, Univ Montpellier, ENSCM, 34000 Montpellier, France.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Dec 22; Vol. 65 (24), pp. 16392-16419. Date of Electronic Publication: 2022 Nov 30.
DOI: 10.1021/acs.jmedchem.2c01257
Abstrakt: Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition ( K i = 10-30 nM). Equilibrium dialysis, native mass spectrometry, isothermal calorimetry (ITC), and X-ray crystallography showed that the compounds inhibited both VIM-2 and NDM-1 at least partially by stripping the catalytic zinc ions. These inhibitors also displayed a very potent synergistic activity with meropenem (16- to 1000-fold minimum inhibitory concentration (MIC) reduction) against VIM-type- and NDM-1-producing ultraresistant clinical isolates, including Enterobacterales and Pseudomonas aeruginosa . Furthermore, selected compounds exhibited no or moderate toxicity toward HeLa cells, favorable absorption, distribution, metabolism, excretion (ADME) properties, and no or modest inhibition of several mammalian metalloenzymes.
Databáze: MEDLINE
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