8BVD

FimH lectin domain in complex with mannose C-linked to quinoline

Summary for 8BVD

• Entry DOI: 10.2210/pdb8bvd/pdb
• Related: 5abz
• Descriptor: Type 1 fimbrin D-mannose specific adhesin, (2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-[(E)-3-quinolin-6-ylprop-2-enyl]oxane-3,4,5-triol (3 entities in total)
• Functional Keywords: type-1 fimbriae, escherichia coli, fimh, adhesin, lectin, anti-adhesives, c-linked mannose, cell adhesion
• Biological source: Escherichia coli UTI89
• Total number of polymer chains: 4
• Total formula weight: 68992.76

Authors

Bouckaert, J.,Bridot, C. (deposition date: 2022-12-03, release date: 2023-02-15, Last modification date: 2024-11-06)

Primary citation

Mousavifar, L.,Sarshar, M.,Bridot, C.,Scribano, D.,Ambrosi, C.,Palamara, A.T.,Vergoten, G.,Roubinet, B.,Landemarre, L.,Bouckaert, J.,Roy, R.
Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists.
Pharmaceutics, 15:-, 2023

PubMed Abstract: Selective antiadhesion antagonists of Uropathogenic (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists based on previously described -linked allyl α-D-mannopyranoside was synthesized using Heck cross-coupling reaction using a series of iodoaryl derivatives. This work reports two new members of FimH antagonist amongst the above family with sub nanomolar affinity. The resulting hydrophobic aglycones, including constrained alkene and aryl groups, were designed to provide additional favorable binding interactions with the so-called FimH "tyrosine gate". The newly synthesized -linked glycomimetic antagonists, having a hydrolytically stable anomeric linkage, exhibited improved binding when compared to previously published analogs, as demonstrated by affinity measurement through interactions by FimH lectin. The crystal structure of FimH co-crystallized with one of the nanomolar antagonists revealed the binding mode of this inhibitor into the active site of the tyrosine gate. In addition, selected mannopyranoside constructs neither affected bacterial growth or cell viability nor interfered with antibiotic activity. -linked mannoside antagonists were effective in decreasing bacterial adhesion to human bladder epithelial cells (HTB-9). Therefore, these molecules constituted additional therapeutic candidates' worth further development in the search for potent anti-adhesive drugs against infections caused by UPEC.

PubMed: 36839848
DOI: 10.3390/pharmaceutics15020527

Experimental method

X-RAY DIFFRACTION (2.995 Å)