6map

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

spinqualitylabelsall models 6map, resolution 1.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6map is a 1 chain structure with sequence from Escherichia coli UTI89. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.08Å Ligands: GOL, JC4, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function YDEQ_ECOLI Publication Abstract from PubMed 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(50) = 0.051 muM) and 90 (IC(50) = 0.034 muM), 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(50) for 6 h. These new FmlH antagonists represent new antivirulence drugs for UTIs. Biphenyl Gal and GalNAc FmlH Lectin Antagonists of Uropathogenic E. coli (UPEC): Optimization through Iterative Rational Drug Design.,Maddirala AR, Klein R, Pinkner JS, Kalas V, Hultgren SJ, Janetka JW J Med Chem. 2019 Jan 24;62(2):467-479. doi: 10.1021/acs.jmedchem.8b01561. Epub , 2019 Jan 2. PMID:30540910 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Adhesin 3D structures

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