Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex

Autor: Hien M. Nguyen, Julie Bouckaert, Stefan Oscarson, Adinda Wellens, Rikard Slättegård, Jean-Pierre Hernalsteens, Lode Wyns, Corinne K. Garofalo, Nani Van Gerven, Henri De Greve, Scott J. Hultgren
Přispěvatelé: Structural Biology Brussels, Department of Bio-engineering Sciences, Ultrastructure, Viral Genetics, Biology
Jazyk: angličtina
Rok vydání: 2008
Předmět:
Glycosylation
Fimbria
Intracellular Space
Mannose
lcsh:Medicine
Oligosaccharides
medicine.disease_cause
Crystallography
X-Ray
Disaccharides
Biochemistry
Pilus
Bacterial Adhesion
Substrate Specificity
Infectious Diseases/Bacterial Infections
chemistry.chemical_compound
Mice
Cystitis
lcsh:Science
Biochemistry/Biomacromolecule-Ligand Interactions
0303 health sciences
Adhesins
Escherichia coli
Multidisciplinary
biology
Agricultural and Biological Sciences(all)
Urology/Urological Infections
3. Good health
Microbiology/Immunity to Infections
Anti-Bacterial Agents
Mannosides
Urinary Tract Infections
ddc:500
Fimbriae Proteins
Biochemistry/Drug Discovery
Asparagine
Research Article
Integrin
Biochemistry/Biomimetic Chemistry
Receptors
Cell Surface
Infectious Diseases/Urological Infections
Microbiology
Cell Line
03 medical and health sciences
Cell Biology/Microbial Growth and Development
medicine
Escherichia coli
Animals
Humans
Cell adhesion
030304 developmental biology
030306 microbiology
Biochemistry
Genetics and Molecular Biology(all)
lcsh:R
Biofilm
Protein Structure
Tertiary
Bacterial adhesin
Cell Biology/Cell Adhesion
Disease Models
Animal
chemistry
Biofilms
Fimbriae
Bacterial
biology.protein
Chemical Biology/Biomimetic Chemistry
lcsh:Q
Biophysics/Biomacromolecule-Ligand Interactions
Zdroj: PLoS ONE
PLoS ONE, Vol 3, Iss 4, p e2040 (2008)
PLoS one 3, e2040 (2008). doi:10.1371/journal.pone.0002040
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0002040
Popis: Background: Escherichia coli strains adhere to the normally sterile human uroepithelium using type 1 pili, that are long, hairy surface organelles exposing a mannose-binding FimH adhesin at the tip. A small percentage of adhered bacteria can successfully invade bladder cells, presumably via pathways mediated by the high-mannosylated uroplakin-Ia and a3b1 integrins found throughout the uroepithelium. Invaded bacteria replicate and mature into dense, biofilm-like inclusions in preparation of fluxing and of infection of neighbouring cells, being the major cause of the troublesome recurrent urinary tract infections. Methodology/Principal Findings: We demonstrate that a-D-mannose based inhibitors of FimH not only block bacterial adhesion on uroepithelial cells but also antagonize invasion and biofilm formation. Heptyl a-D-mannose prevents binding of type 1-piliated E. coli to the human bladder cell line 5637 and reduces both adhesion and invasion of the UTI89 cystitis isolate instilled in mouse bladder via catheterization. Heptyl a-D-mannose also specifically inhibited biofilm formation at micromolar concentrations. The structural basis of the great inhibitory potential of alkyl and aryl a-D-mannosides was elucidated in the crystal structure of the FimH receptor-binding domain in complex with oligomannose-3. FimH interacts with Mana1,3Manb1,4GlcNAcb1,4GlcNAc in an extended binding site. The interactions along the a1,3 glycosidic bond and the first b1,4 linkage to the chitobiose unit are conserved with those of FimH with butyl a-D-mannose. The strong stacking of the central mannose with the aromatic ring of Tyr48 is congruent with the high affinity found for synthetic inhibitors in which this mannose is substituted for by an aromatic group. Conclusions/Significance: The potential of ligand-based design of antagonists of urinary tract infections is ruled by the structural mimicry of natural epitopes and extends into blocking of bacterial invasion, intracellular growth and capacity to fluxing and of recurrence of the infection.
Databáze: OpenAIRE
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