6MAW

F9 Pilus Adhesin FmlH Lectin Domain from E. coli UTI89 in Complex with Galactoside N-[(2S,3R,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-{[S-methyl-6-(trifluoromethyl)-[1,1'-biphenyl]-3'-yl]oxy}oxan-3-yl]acetamide

6MAW の概要

• エントリーDOI: 10.2210/pdb6maw/pdb
• 分子名称: Fimbrial adhesin FmlD, N-[2'-{[2-(acetylamino)-2-deoxy-beta-D-galactopyranosyl]oxy}-6'-(trifluoromethyl)[1,1'-biphenyl]-3-yl]methanesulfonamide (3 entities in total)
• 機能のキーワード: pilus, adhesin, galactose, lectin, sugar binding protein, sugar binding protein-inhibitor complex, sugar binding protein/inhibitor
• 由来する生物種: Escherichia coli UTI89
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18454.59

構造登録者

Klein, R.D.,Hultgren, S.J. (登録日: 2018-08-28, 公開日: 2019-09-04, 最終更新日: 2024-11-06)

主引用文献

Maddirala, A.R.,Klein, R.,Pinkner, J.S.,Kalas, V.,Hultgren, S.J.,Janetka, J.W.
Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design.
J.Med.Chem., 62:467-479, 2019

PubMed Abstract: The F9/Yde/Fml pilus, tipped with the FmlH adhesin, has been shown to provide uropathogenic Escherichia coli (UPEC) a fitness advantage in urinary tract infections (UTIs). Here, we used X-ray structure guided design to optimize our previously described ortho-biphenyl Gal and GalNAc FmlH antagonists such as compound 1 by replacing the carboxylate with a sulfonamide as in 50. Other groups which can accept H-bonds were also tolerated. We pursued further modifications to the biphenyl aglycone resulting in significantly improved activity. Two of the most potent compounds, 86 (IC = 0.051 μM) and 90 (IC = 0.034 μM), exhibited excellent metabolic stability in mouse plasma and liver microsomes but showed only limited oral bioavailability (<1%) in rats. Compound 84 also showed a good pharmacokinetic (PK) profile in mice after IP dosing with compound exposure above the IC for 6 h. These new FmlH antagonists represent new antivirulence drugs for UTIs.

PubMed: 30540910
DOI: 10.1021/acs.jmedchem.8b01561

実験手法

X-RAY DIFFRACTION (1.75 Å)