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dc.contributor.authorKlein, Raphaelen_US
dc.contributor.authorLinciano, Pasqualeen_US
dc.contributor.authorCelenza, Guiseppeen_US
dc.contributor.authorBellio, Pierangeloen_US
dc.contributor.authorPapaioannou, Sofiaen_US
dc.contributor.authorBlazques, Jesusen_US
dc.contributor.authorCendron, Lauraen_US
dc.contributor.authorBrenk, Ruthen_US
dc.contributor.authorTondi, Donatellaen_US
dc.PublishedKlein, Linciano, Celenza, Bellio, Papaioannou, Blazques, Cendron, Brenk R, Tondi. In silico identification and experimental validation of hits active against KPC-2 β-lactamase. PLoS ONE. 2018;13(11):e0203241eng
dc.description.abstractBacterial resistance has become a worldwide concern, particularly after the emergence of resistant strains overproducing carbapenemases. Among these, the KPC-2 carbapenemase represents a significant clinical challenge, being characterized by a broad substrate spectrum that includes aminothiazoleoxime and cephalosporins such as cefotaxime. Moreover, strains harboring KPC-type β-lactamases are often reported as resistant to available β-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam). Therefore, the identification of novel non β-lactam KPC-2 inhibitors is strongly necessary to maintain treatment options. This study explored novel, non-covalent inhibitors active against KPC-2, as putative hit candidates. We performed a structure-based in silico screening of commercially available compounds for non-β-lactam KPC-2 inhibitors. Thirty-two commercially available high-scoring, fragment-like hits were selected for in vitro validation and their activity and mechanism of action vs the target was experimentally evaluated using recombinant KPC-2. N-(3-(1H-tetrazol-5-yl)phenyl)-3-fluorobenzamide (11a), in light of its ligand efficiency (LE = 0.28 kcal/mol/non-hydrogen atom) and chemistry, was selected as hit to be directed to chemical optimization to improve potency vs the enzyme and explore structural requirement for inhibition in KPC-2 binding site. Further, the compounds were evaluated against clinical strains overexpressing KPC-2 and the most promising compound reduced the MIC of the β-lactam antibiotic meropenem by four-fold.en_US
dc.rightsAttribution CC BYeng
dc.titleIn silico identification and experimental validation of hits active against KPC-2 β-lactamaseen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2018 The Author(s)
dc.source.journalPLoS ONE

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