Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin

Bouckaert, Julie, Berglund, Jenny, Schembri, Mark, De Genst, Erwin, Cool, Lieve, Wuhrer, Manfred, Hung, Chia-Suei, Pinkner, Jerome, Slattegard, Rikard, Zavialov, Anton, Choudhury, Devapriya, Langermann, Solomon, Hultgren, Scott J., Wyns, Lode and Klemm, Per (2005) Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Molecular Microbiology, 55 2: 441-455. doi:10.1111/j.1365-2958.2004.04415.x


Author Bouckaert, Julie
Berglund, Jenny
Schembri, Mark
De Genst, Erwin
Cool, Lieve
Wuhrer, Manfred
Hung, Chia-Suei
Pinkner, Jerome
Slattegard, Rikard
Zavialov, Anton
Choudhury, Devapriya
Langermann, Solomon
Hultgren, Scott J.
Wyns, Lode
Klemm, Per
Title Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin
Journal name Molecular Microbiology   Check publisher's open access policy
ISSN 0950-382X
Publication date 2005-01-01
Sub-type Article (original research)
DOI 10.1111/j.1365-2958.2004.04415.x
Volume 55
Issue 2
Start page 441
End page 455
Total pages 15
Place of publication Oxford
Publisher Blackwell Scientific Publications
Language eng
Subject C1
270301 Bacteriology
780105 Biological sciences
Abstract Mannose-binding type 1 pili are important virulence factors for the establishment of Escherichia coli urinary tract infections (UTIs). These infections are initiated by adhesion of uropathogenic E. coli to uroplakin receptors in the uroepithelium via the FimH adhesin located at the tips of type 1 pili. Blocking of bacterial adhesion is able to prevent infection. Here, we provide for the first time binding data of the molecular events underlying type 1 fimbrial adherence, by crystallographic analyses of the FimH receptor binding domains from a uropathogenic and a K-12 strain, and affinity measurements with mannose, common mono- and disaccharides, and a series of alkyl and aryl mannosides. Our results illustrate that the lectin domain of the FimH adhesin is a stable and functional entity and that an exogenous butyl alpha- D-mannoside, bound in the crystal structures, exhibits a significantly better affinity for FimH (K-d = 0.15 muM) than mannose (K-d = 2.3 muM). Exploration of the binding affinities of alpha-D-mannosides with longer alkyl tails revealed affinities up to 5 nM. Aryl mannosides and fructose can also bind with high affinities to the FimH lectin domain, with a 100-fold improvement and 15-fold reduction in affinity, respectively, compared with mannose. Taken together, these relative FimH affinities correlate exceptionally well with the relative concentrations of the same glycans needed for the inhibition of adherence of type 1 piliated E. coli. We foresee that our findings will spark new ideas and initiatives for the development of UTI vaccines and anti-adhesive drugs to prevent anticipated and recurrent UTIs.
Keyword Biochemistry & Molecular Biology
Microbiology
Urinary-tract-infection
Drives Fiber Formation
Structural Basis
Type-1 Fimbriae
Pilus Biogenesis
Molecular Replacement
Urothelial Receptor
Chaperone Function
Biofilm Formation
Epithelial-cells
Q-Index Code C1
Additional Notes Authors of this document: Bouckaert, J; Berglund, J; Schembri, M; De Genst, E; Cools, L; Wuhrer, M; Hung, CS; Pinkner, J; Slattegard, R; Zavialov, A; Choudhury, D; Langermann, S; Hultgren, SJ; Wyns, L; Klemm, P; Oscarson, S; Knight, SD; De Greve, H. DOI: 10.1111/j.1365-2958.2004.04415.x

 
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Created: Wed, 15 Aug 2007, 16:26:24 EST