4LEN

CTX-M-9 in complex with the broad spectrum inhibitor 3-(2- carboxyvinyl)benzo(b)thiophene-2-boronic acid

4LEN の概要

• エントリーDOI: 10.2210/pdb4len/pdb
• 分子名称: Beta-lactamase, (2E)-3-[2-(dihydroxyboranyl)-1-benzothiophen-3-yl]prop-2-enoic acid (3 entities in total)
• 機能のキーワード: binding sites, structure base drug design, drug discovery, molecular, enzyme inhibitors, beta lactamases, boronic acids, broad spectrum, bacterial resistance, double perturbation cycle analysis, thermodynamics, structure activity relationship, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56441.11

構造登録者

Tondi, D. (登録日: 2013-06-26, 公開日: 2014-06-18, 最終更新日: 2024-10-16)

主引用文献

Tondi, D.,Venturelli, A.,Bonnet, R.,Pozzi, C.,Shoichet, B.K.,Costi, M.P.
Targeting Class A and C Serine beta-Lactamases with a Broad-Spectrum Boronic Acid Derivative.
J.Med.Chem., 57:5449-5458, 2014

PubMed Abstract: Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.

PubMed: 24882105
DOI: 10.1021/jm5006572

実験手法

X-RAY DIFFRACTION (1.5 Å)