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Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC‐2: A Step against Bacterial Resistance
Author(s) -
Celenza Giuseppe,
Vicario Mattia,
Bellio Pierangelo,
Linciano Pasquale,
Perilli Mariagrazia,
Oliver Antonio,
Blazquez Jesús,
Cendron Laura,
Tondi Donatella
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700788
Subject(s) - phenylboronic acid , chemistry , antibiotic resistance , bacteria , microbiology and biotechnology , combinatorial chemistry , biology , stereochemistry , biochemistry , genetics , antibiotics , catalysis
The emergence and dissemination of multidrug resistant (MDR) pathogens resistant to nearly all available antibiotics poses a significant threat in clinical therapy. Among them, Klebsiella pneumoniae clinical isolates overexpressing KPC‐2 carbapenemase are the most worrisome, extending bacterial resistance to last‐resort carbapenems. In this study, we investigate the molecular recognition requirements in the KPC‐2 active site by small phenylboronic acid derivatives. Four new phenylboronic acid derivatives were designed and tested against KPC‐2. For the most active, despite their simple chemical structures, nanomolar affinity was achieved. The new derivatives restored susceptibility to meropenem in clinical strains overexpressing KPC‐2. Moreover, no cytotoxicity was detected in cell‐viability assays, which further validated the designed leads. Two crystallographic binary complexes of the best inhibitors binding KPC‐2 were obtained at high resolution. Kinetic descriptions of slow binding, time‐dependent inhibition, and interaction geometries in KPC‐2 were fully investigated. This study will ultimately lead toward the optimization and development of more‐effective KPC‐2 inhibitors.