5LL7

Crystal structure of KPC-2 carbapenemase in complex with a phenyl boronic inhibitor.

5LL7 の概要

• エントリーDOI: 10.2210/pdb5ll7/pdb
• 関連するPDBエントリー: 5MGI
• 分子名称: Beta-lactamase, (~{E})-3-[2-(dihydroxyboranyl)phenyl]prop-2-enoic acid, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: carbapenemase, beta-lactamase, phenyl boronic inhibitor, hydrolase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28769.10

構造登録者

Vicario, M.,Celenza, G.,Bellio, P.,Perilli, M.G.,Tondi, D.,Cendron, L. (登録日: 2016-07-26, 公開日: 2018-02-21, 最終更新日: 2024-10-16)

主引用文献

Celenza, G.,Vicario, M.,Bellio, P.,Linciano, P.,Perilli, M.,Oliver, A.,Blazquez, J.,Cendron, L.,Tondi, D.
Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step against Bacterial Resistance.
Chemmedchem, 13:713-724, 2018

PubMed 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.

PubMed: 29356380
DOI: 10.1002/cmdc.201700788

実験手法

X-RAY DIFFRACTION (1.4 Å)