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9CCY

Crystal structure of the Klebsiella pneumoniae LpxH / JH-LPH-90 complex

これはPDB形式変換不可エントリーです。
9CCY の概要
エントリーDOI10.2210/pdb9ccy/pdb
分子名称UDP-2,3-diacylglucosamine hydrolase, 1-(5-{4-[6-(trifluoromethyl)pyridin-2-yl]piperazine-1-sulfonyl}-2,3-dihydro-1H-indol-1-yl)ethan-1-one, MANGANESE (II) ION, ... (4 entities in total)
機能のキーワードlpxh, lipid a, antibiotic, inhibitor
由来する生物種Klebsiella pneumoniae
タンパク質・核酸の鎖数1
化学式量合計30192.02
構造登録者
Cochrane, C.S.,Zhou, P. (登録日: 2024-06-23, 公開日: 2025-02-12)
主引用文献Ennis, A.F.,Cochrane, C.S.,Dome, P.A.,Jeong, P.,Yu, J.,Lee, H.,Williams, C.S.,Ha, Y.,Yang, W.,Zhou, P.,Hong, J.
Design and Evaluation of Pyridinyl Sulfonyl Piperazine LpxH Inhibitors with Potent Antibiotic Activity Against Enterobacterales.
Jacs Au, 4:4383-4393, 2024
Cited by
PubMed Abstract: Enterobacterales, a large order of Gram-negative bacteria, including and , are major causes of urinary tract and gastrointestinal infections, pneumonia, and other diseases in healthcare settings and communities. ESBL-producing Enterobacterales and carbapenem-resistant Enterobacterales can break down commonly used antibiotics, with some strains being resistant to all available antibiotics. This public health threat necessitates the development of novel antibiotics, ideally targeting new pathways in these bacteria. Gram-negative bacteria possess an outer membrane enriched with lipid A, a saccharolipid that serves as the membrane anchor of lipopolysaccharides and the active component of the bacterial endotoxin, causing septic shock. The biosynthesis of lipid A is crucial for the viability of Gram-negative bacteria, and as an essential enzyme in this process, LpxH has emerged as a promising target for developing novel antibiotics against multidrug-resistant Gram-negative pathogens. Here, we report the development of pyridinyl sulfonyl piperazine LpxH inhibitors. Among them, -substituted pyridinyl compounds significantly boost LpxH inhibition and antibiotic activity over the original phenyl series. Structural and QM/MM analyses reveal that these improved activities are primarily due to the enhanced interaction between F141 of the LpxH insertion lid and the pyridinyl group. Incorporation of the -methyl--phenyl-methanesulfonamide moiety into the pyridinyl sulfonyl piperazine backbone results in JH-LPH-106 and JH-LPH-107, both of which exhibit potent antibiotic activity against wild-type Enterobacterales such as and . JH-LPH-107 exhibits a low rate of spontaneous resistance and a high safety window , rendering it an excellent lead for further clinical development.
PubMed: 39610720
DOI: 10.1021/jacsau.4c00731
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (2.05 Å)
構造検証レポート
Validation report summary of 9ccy
検証レポート(詳細版)ダウンロードをダウンロード

238582

件を2025-07-09に公開中

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