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Título: | Phenylboronic acids probing molecular recognition against class A and class C β-lactamases |
Autor: | Linciano, Pasquale; Vicario, Mattia; Kekez, Ivana; Bellio, Pierangelo; Celenza, Giuseppe; Martín-Blecua, Isabel; Blázquez Gómez, Jesús CSIC ORCID; Cendron, Laura; Tondi, Donatella | Palabras clave: | Serine β-lactamases Carbapenemases KPC-2 Klebsiella pneumoniae GES-5 Guyana extended-spectrum-lactamase Boronic acid enzyme inhibitors X-ray crystallography synergism |
Fecha de publicación: | 30-sep-2019 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | Antibiotics 8(4): 171 (2019) | Resumen: | Worldwide dissemination of pathogens resistant to almost all available antibiotics represent a real problem preventing efficient treatment of infectious diseases. Among antimicrobial used in therapy, β-lactam antibiotics represent 40% thus playing a crucial role in the management of infections treatment. We report a small series of phenylboronic acids derivatives (BAs) active against class A carbapenemases KPC-2 and GES-5, and class C cephalosporinases AmpC. The inhibitory profile of our BAs against class A and C was investigated by means of molecular docking, enzyme kinetics and X-ray crystallography. We were interested in the mechanism of recognition among class A and class C to direct the design of broad serine β-Lactamases (SBLs) inhibitors. Molecular modeling calculations vs GES-5 and crystallographic studies vs AmpC reasoned, respectively, the ortho derivative <b>2</b> and the meta derivative <b>3</b> binding affinity. The ability of our BAs to protect β-lactams from BLs hydrolysis was determined in biological assays conducted against clinical strains: Fractional inhibitory concentration index (FICI) tests confirmed their ability to be synergic with β-lactams thus restoring susceptibility to meropenem. Considering the obtained results and the lack of cytotoxicity, our derivatives represent validated probe for the design of SBLs inhibitors. | Versión del editor: | https://doi.org/10.3390/antibiotics8040171 | URI: | http://hdl.handle.net/10261/197196 | DOI: | 10.3390/antibiotics8040171 | E-ISSN: | 2079-6382 |
Aparece en las colecciones: | (CNB) Artículos |
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phenylboronic_acids_molecular_recognition_class_A_C_β-lactamases.pdf | 4,05 MB | Adobe PDF | Visualizar/Abrir |
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