Article (Périodiques scientifiques)
Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors
Sgrignani, J.; De Luca, F.; Torosyan, H. et al.
2016In Journal of Computer-Aided Molecular Design, 30 (10), p. 851-861
Peer reviewed vérifié par ORBi
 

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Mots-clés :
Antibiotic resistance; Beta-lactamase; Boronic acids; Carbapenemase; Docking; Extended-spectrum β-lactamase; Virtual screening; AmpC beta-lactamases; Article; Enterobacter; Escherichia coli; Bacterial Proteins; Binding Sites; Computer Simulation; Drug Discovery; Models, Molecular; Protein Binding; Protein Conformation; Serine
Résumé :
[en] β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of ~1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar Ki value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase. © 2016, Springer International Publishing Switzerland.
Disciplines :
Microbiologie
Biochimie, biophysique & biologie moléculaire
Auteur, co-auteur :
Sgrignani, J.;  ICRM-CNR, Via Mario Bianco 9, Milan, 20131, Italy, Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Via Vincenzo Vela 6, Bellinzona, 6500, Switzerland
De Luca, F.;  Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico “Le Scotte”, Viale Bracci 16, Siena, 53100, Italy
Torosyan, H.;  Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA 94158, United States
Docquier, Jean-Denis ;  Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines
Duan, D.;  Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA 94158, United States
Novati, B.;  Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, Milan, 20133, Italy
Prati, F.;  Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via G. Campi 103, Modena, 41125, Italy
Colombo, G.;  ICRM-CNR, Via Mario Bianco 9, Milan, 20131, Italy
Grazioso, G.;  Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, Milan, 20133, Italy
Langue du document :
Anglais
Titre :
Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors
Date de publication/diffusion :
2016
Titre du périodique :
Journal of Computer-Aided Molecular Design
ISSN :
0920-654X
eISSN :
1573-4951
Maison d'édition :
Springer
Volume/Tome :
30
Fascicule/Saison :
10
Pagination :
851-861
Peer reviewed :
Peer reviewed vérifié par ORBi
Organisme subsidiant :
Regione Lombardia
AIRC - Associazione Italiana per la Ricerca sul Cancro
Disponible sur ORBi :
depuis le 19 novembre 2020

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