5F3F

Crystal structure of para-biphenyl-2-methyl-3'-methyl amide mannoside bound to FimH lectin domain

5F3F の概要

• エントリーDOI: 10.2210/pdb5f3f/pdb
• 関連するPDBエントリー: 5F2F
• 分子名称: Protein FimH, 3-[4-[(2~{R},3~{S},4~{S},5~{S},6~{R})-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-3-methyl-phenyl]-~{N}-methyl-benzamide (3 entities in total)
• 機能のキーワード: mannoside, fimh, adhesin, carbohydrate binding protein, sugar binding protein
• 由来する生物種: Escherichia coli J96
• 細胞内の位置: Fimbrium: P08191
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17320.25

構造登録者

Klein, R.D.,Hultgren, S.J. (登録日: 2015-12-02, 公開日: 2016-12-07, 最終更新日: 2024-10-30)

主引用文献

Mydock-McGrane, L.,Cusumano, Z.,Han, Z.,Binkley, J.,Kostakioti, M.,Hannan, T.,Pinkner, J.S.,Klein, R.,Kalas, V.,Crowley, J.,Rath, N.P.,Hultgren, S.J.,Janetka, J.W.
Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections.
J.Med.Chem., 59:9390-9408, 2016

PubMed Abstract: Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.

PubMed: 27689912
DOI: 10.1021/acs.jmedchem.6b00948

実験手法

X-RAY DIFFRACTION (1.76 Å)