4XUX

Structure of ampC bound to RPX-7009 at 1.75 A

4XUX の概要

• エントリーDOI: 10.2210/pdb4xux/pdb
• 関連するPDBエントリー: 4XUZ
• 分子名称: Beta-lactamase, Vaborbactam, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: hydrolase-antibiotic complex, hydrolase/antibiotic
• 由来する生物種: Enterobacter cloacae
• 細胞内の位置: Periplasm : P05364
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39955.31

構造登録者

Clifton, M.C.,Abendroth, J. (登録日: 2015-01-26, 公開日: 2015-04-01, 最終更新日: 2024-11-06)

主引用文献

Hecker, S.J.,Reddy, K.R.,Totrov, M.,Hirst, G.C.,Lomovskaya, O.,Griffith, D.C.,King, P.,Tsivkovski, R.,Sun, D.,Sabet, M.,Tarazi, Z.,Clifton, M.C.,Atkins, K.,Raymond, A.,Potts, K.T.,Abendroth, J.,Boyer, S.H.,Loutit, J.S.,Morgan, E.E.,Durso, S.,Dudley, M.N.
Discovery of a Cyclic Boronic Acid beta-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.
J.Med.Chem., 58:3682-3692, 2015

PubMed Abstract: The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.

PubMed: 25782055
DOI: 10.1021/acs.jmedchem.5b00127

実験手法

X-RAY DIFFRACTION (1.75 Å)