Bacterial 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.
|Data di pubblicazione:||2018|
|Titolo:||In Silico Identification and In Vitro Validation of Novel KPC-2 β-lactamase Inhibitors|
|Autore/i:||Klein, Raphael; Linciano, Pasquale; Celenza, Giuseppe; Bellio, Pierangelo; Papaioannou, Sofia; Blazquez, Jesus; Cendron, Laura; Brenk, Ruth; Tondi, Donatella|
|Digital Object Identifier (DOI):||10.1101/396283|
|Codice identificativo Scopus:||2-s2.0-85057557098|
|Citazione:||In Silico Identification and In Vitro Validation of Novel KPC-2 β-lactamase Inhibitors / Klein, Raphael; Linciano, Pasquale; Celenza, Giuseppe; Bellio, Pierangelo; Papaioannou, Sofia; Blazquez, Jesus; Cendron, Laura; Brenk, Ruth; Tondi, Donatella. - In: PLOS ONE. - ISSN 1932-6203. - (2018), pp. 1-20.|
|Tipologia||Articolo su rivista|
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