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The Conformational Variability of FimH: Which Conformation Represents the Therapeutic Target?

Eris, Deniz and Preston, Roland C. and Scharenberg, Meike and Hulliger, Fabian and Abgottspon, Daniela and Pang, Lijuan and Jiang, Xiaohua and Schwardt, Oliver and Ernst, Beat. (2016) The Conformational Variability of FimH: Which Conformation Represents the Therapeutic Target? ChemBioChem, 17 (11). pp. 1012-1020.

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Official URL: http://edoc.unibas.ch/52925/

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Abstract

FimH is a bacterial lectin found at the tips of type 1 pili of uropathogenic Escherichia coli (UPEC). It mediates shear-enhanced adhesion to mannosylated surfaces. Binding of UPEC to urothelial cells initiates the infection cycle leading to urinary tract infections (UTIs). Antiadhesive glycomimetics based on α-d-mannopyranose offer an attractive alternative to the conventional antibiotic treatment because they do not induce a selection pressure and are therefore expected to have a reduced resistance potential. Genetic variation of the fimH gene in clinically isolated UPEC has been associated with distinct mannose binding phenotypes. For this reason, we investigated the mannose binding characteristics of four FimH variants with mannose-based ligands under static and hydrodynamic conditions. The selected FimH variants showed individually different binding behavior under both sets of conditions as a result of the conformational variability of FimH. Clinically relevant FimH variants typically exist in a dynamic conformational equilibrium. Additionally, we evaluated inhibitory potencies of four FimH antagonists representing different structural classes. Inhibitory potencies of three of the tested antagonists were dependent on the binding phenotype and hence on the conformational equilibrium of the FimH variant. However, the squarate derivative was the notable exception and inhibited FimH variants irrespective of their binding phenotype. Information on antagonist affinities towards various FimH variants has remained largely unconsidered despite being essential for successful antiadhesion therapy.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Ernst, Beat and Preston, Roland and Scharenberg, Meike and Abgottspon, Daniela and Pang, Lijuan and Jiang, Xiaohua and Schwardt, Oliver
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:1439-4227
e-ISSN:1439-7633
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:28 Nov 2017 11:12
Deposited On:26 Oct 2017 14:57

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