5F2F

Crystal structure of para-biphenyl-2-methyl-3', 5' di-methyl amide mannoside bound to FimH lectin domain

Summary for 5F2F

• Entry DOI: 10.2210/pdb5f2f/pdb
• Descriptor: Protein FimH, 5-[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}1,~{N}3-dimethyl-benzene-1,3-dicarboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: lectin, mannoside, immunoglobulin fold, carbohydrate binding protein, sugar binding protein
• Biological source: Escherichia coli J96
• Total number of polymer chains: 1
• Total formula weight: 17561.49

Authors

Kalas, V.,Hultgren, S.J. (deposition date: 2015-12-01, release date: 2016-05-04, Last modification date: 2024-10-16)

Primary citation

Jarvis, C.,Han, Z.,Kalas, V.,Klein, R.,Pinkner, J.S.,Ford, B.,Binkley, J.,Cusumano, C.K.,Cusumano, Z.,Mydock-McGrane, L.,Hultgren, S.J.,Janetka, J.W.
Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI.
Chemmedchem, 11:367-373, 2016

PubMed Abstract: Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo. In a rational design strategy, we obtained an X-ray structure of lead mannosides and then designed mannosides with improved drug-like properties. We show that cyclizing the carboxamide onto the biphenyl B-ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2-methyl-4-(1-oxo-1,2-dihydroisoquinolin-7-yl)phenyl α-d-mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N-Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22, as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria-mediated hemagglutination and prevent biofilm formation by UPEC with single-digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.

PubMed: 26812660
DOI: 10.1002/cmdc.201600006

Experimental method

X-RAY DIFFRACTION (1.665 Å)