title: The Conformational Variability of FimH: Which Conformation Represents the Therapeutic Target?
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.
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Deniz
authors.initials: D
authors.lastname: Eris
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Roland C
authors.initials: RC
authors.lastname: Preston
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Meike
authors.initials: M
authors.lastname: Scharenberg
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hulliger
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Abgottspon
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Pang
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.affiliation: Department of Pharmaceutical Sciences, Institute of Molecular Pharmacy, Pharmacenter, Klingelbergstrasse 50, 4056, Basel, Switzerland. beat.ernst@unibas.ch.
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D018830:Adhesins, Escherichia coli / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000302:isolation & purification / Q000378:metabolism; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008358:Mannose / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014552:Urinary Tract Infections / Q000382:microbiology / Q000473:pathology; D060167:Uroplakin Ia / Q000737:chemistry / Q000378:metabolism
chemical_list: D018830:Adhesins, Escherichia coli; D060167:Uroplakin Ia; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008358:Mannose
keywords: FimH; catch-bonds; cell adhesion; conformational variability; inhibitors