Unknown

Dataset Information

0

In silico identification and experimental validation of hits active against KPC-2 ?-lactamase.


ABSTRACT: 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 ?-lactamases are often reported as resistant to available ?-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam). Therefore, the identification of novel non ?-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-?-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 ?-lactam antibiotic meropenem by four-fold.

SUBMITTER: Klein R 

PROVIDER: S-EPMC6264499 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

altmetric image

Publications

In silico identification and experimental validation of hits active against KPC-2 β-lactamase.

Klein Raphael R   Linciano Pasquale P   Celenza Giuseppe G   Bellio Pierangelo P   Papaioannou Sofia S   Blazquez Jesus J   Cendron Laura L   Brenk Ruth R   Tondi Donatella D  

PloS one 20181129 11


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 sulbacta  ...[more]

Similar Datasets

| S-EPMC2655312 | biostudies-literature
| S-EPMC9745794 | biostudies-literature
| S-EPMC10215400 | biostudies-literature
| S-EPMC2812178 | biostudies-literature
| S-EPMC2769493 | biostudies-literature
| S-EPMC4131836 | biostudies-other
| S-EPMC7536818 | biostudies-literature
| S-EPMC3102533 | biostudies-literature
| S-EPMC5971601 | biostudies-literature
| S-EPMC10480165 | biostudies-literature