Phenylboronic Acids Probing Molecular Recognition against Class A and Class C β-lactamases

• Main Authors: Pasquale Linciano, Mattia Vicario, Ivana Kekez, Pierangelo Bellio, Giuseppe Celenza, Isabel Martín-Blecua, Jesús Blázquez, Laura Cendron, Donatella Tondi
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: Antibiotics
• Subjects: serine β-lactamases; carbapenemases; kpc-2 klebsiella pneumoniae; ges-5 guyana extended-spectrum-lactamase; boronic acid; enzyme inhibitors; x-ray crystallography; synergism
• Online Access: https://www.mdpi.com/2079-6382/8/4/171

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, &#946;-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 &#946;-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 &#946;-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 &#946;-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.