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Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step Against Bacterial Resistance

Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step Against Bacterial Resistance

Giuseppe Celenza, Mattia Vicario, Pierangelo Bellio, Pasquale Linciano, Mariagrazia Perilli, Antonio Oliver, Jesús Blazquez, Laura Cendron, Donatella Tondi

ChemMedChem. 2018 Apr 6;13(7):713-724.

PMID: 29356380

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP849062233	3-Bromo-5-methyl-2-(3′-methoxybenzyloxy)phenylboronic acid		849062-23-3	Price
AP870779014	2-(4′-Fluorobenzyloxy)phenylboronic acid		870779-01-4	Price

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