2I72

AmpC beta-lactamase in complex with 5-diformylaminomethyl-benzo[b]thiophen-2-boronic acid

2I72 の概要

• エントリーDOI: 10.2210/pdb2i72/pdb
• 関連するPDBエントリー: 1CB3 1KE4
• 分子名称: Beta-lactamase, {5-[(DIFORMYLAMINO)METHYL]-1-BENZOTHIEN-2-YL}BORONIC ACID (3 entities in total)
• 機能のキーワード: ampc, beta-lactamase, cephalosporinase, serine hydrolase, hydrolase
• 由来する生物種: Escherichia coli
• 細胞内の位置: Periplasm: P00811
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79702.00

構造登録者

Venturelli, A.,Cancian, L.,Tondi, D.,Morandi, F.,Cannazza, G.,Segatore, B.,Prati, F.,Amicosante, G.,Shoichet, B.K.,Costi, M.P. (登録日: 2006-08-30, 公開日: 2007-09-11, 最終更新日: 2024-10-30)

主引用文献

Venturelli, A.,Tondi, D.,Cancian, L.,Morandi, F.,Cannazza, G.,Segatore, B.,Prati, F.,Amicosante, G.,Shoichet, B.K.,Costi, M.P.
Optimizing Cell Permeation of an Antibiotic Resistance Inhibitor for Improved Efficacy
J.Med.Chem., 50:5644-5654, 2007

PubMed Abstract: Benzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C beta-lactamase AmpC and potentiates the activity of beta-lactam antibiotics in bacteria that express this and related enzymes. As is often true, the potency of compound 1 against the enzymes is much attenuated in cell culture against Gram negative bacteria, where the minimum inhibitor concentration of compound 1 is in the mid-micromolar range. Here, we modulated the properties of this lead to enhance its ability to cross the membrane, using a combination of X-ray crystallography, structure-based design, and application of physical models of outer membrane crossing. This strategy led us to derivatives with substantially improved permeability. Also, the greater solubility of these compounds allowed us to measure their efficacy at higher concentrations than with the lead 1, leading to higher maximum potentiation of the antibiotic effect of ceftazidime on resistant bacteria.

PubMed: 17956081
DOI: 10.1021/jm070643q

実験手法

X-RAY DIFFRACTION (2.2 Å)