title: Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors.
abstract: 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 Kivalue 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.
authors.affiliation: ICRM-CNR, Via Mario Bianco 9, 20131, Milan, Italy.|Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Via Vincenzo Vela 6, 6500, Bellinzona, Switzerland.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Sgrignani
authors.affiliation: Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico "Le Scotte", Viale Bracci 16, 53100, Siena, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: De Luca
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA, 94158, USA.
authors.forename: Hayarpi
authors.initials: H
authors.lastname: Torosyan
authors.affiliation: Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico "Le Scotte", Viale Bracci 16, 53100, Siena, Italy.
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Docquier
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA, 94158, USA.
authors.forename: Da
authors.initials: D
authors.lastname: Duan
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133, Milan, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Novati
authors.affiliation: Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via G. Campi 103, 41125, Modena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
authors.affiliation: ICRM-CNR, Via Mario Bianco 9, 20131, Milan, Italy. giorgio.colombo@icrm.cnr.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133, Milan, Italy. giovanni.grazioso@unimi.it.
authors.forename: Giovanni
authors.identifier: 0000-0002-3261-9356
authors.initials: G
authors.lastname: Grazioso
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D001897:Boronic Acids / Q000737:chemistry*; D003198:Computer Simulation; D055808:Drug Discovery; D004754:Enterobacter / Q000201:enzymology; D004926:Escherichia coli / Q000201:enzymology; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012694:Serine / Q000737:chemistry; D065093:beta-Lactamase Inhibitors / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D001897:Boronic Acids; D065093:beta-Lactamase Inhibitors; D012694:Serine; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; C063912:carbapenemase; C010686:benzeneboronic acid
keywords: Antibiotic resistance; Beta-lactamase; Boronic acids; Carbapenemase; Docking; Extended-spectrum β-lactamase; Virtual screening