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Intervening with Urinary Tract Infections Using Anti-Adhesives Based on the Crystal Structure of the FimH–Oligomannose-3 Complex
Journal Contribution - Journal Article
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.
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.
Journal: PLOS ONE
ISSN: 1932-6203
Volume: 30
Pages: 2040
Publication year:2008
Keywords:Urinary tract infection, Anti-adhesives, Type 1 fimbriae, FimH adhesin