5F2F: Crystal structure of para-biphenyl-2-methyl-3', 5' di-methyl amide mannoside bound to FimH lectin domain

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 alpha-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.
PDB ID: 5F2FDownload
MMDB ID: 138947
PDB Deposition Date: 2015/12/1
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 1.665  Å
Source Organism:
Similar Structures:
Biological Unit for 5F2F: monomeric; determined by author and by software (PISA)
Molecular Components in 5F2F
Label Count Molecule
Protein (1 molecule)
Protein Fimh(Gene symbol: fimH)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

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