Abstract
The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is the adhesion of bacteria to urothelial cells. This attachment is mediated by FimH, a mannose-binding adhesin, which is expressed on the bacterial surface. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials. Therefore, new treatment strategies are urgently needed, avoiding selection pressure and thereby implying a reduced risk of resistance. Here, we present a new class of highly active antimicrobials, targeting the virulence factor FimH. When the most potent representative, an indolinylphenyl mannoside, was administered in a mouse model at the low dosage of 1 mg/kg (corresponding to approximately 25 μg/mouse), the minimal therapeutic concentration to prevent UTI was maintained for more than 8 h. In a treatment study, the colony-forming units in the bladder could be reduced by almost 4 orders of magnitude, comparable to the standard antibiotic treatment with ciprofloxacin (8 mg/kg, sc).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adhesins, Escherichia coli
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Animals
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Anti-Infective Agents, Urinary / chemical synthesis
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Anti-Infective Agents, Urinary / pharmacokinetics
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Anti-Infective Agents, Urinary / pharmacology*
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Bacterial Adhesion / drug effects*
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Benzene Derivatives / chemical synthesis
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Benzene Derivatives / pharmacokinetics
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Benzene Derivatives / pharmacology*
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Cell Line
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Escherichia coli Infections / drug therapy*
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Escherichia coli Infections / enzymology
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Fimbriae Proteins / antagonists & inhibitors*
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Indoles / chemical synthesis
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Kidney / drug effects
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Kidney / microbiology
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Mannosides / chemical synthesis
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Mannosides / pharmacokinetics
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Mannosides / pharmacology*
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Mice
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Microbial Sensitivity Tests
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Structure-Activity Relationship
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Urinary Bladder / drug effects
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Urinary Bladder / microbiology
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Urinary Tract Infections / drug therapy*
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Urinary Tract Infections / enzymology
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Uropathogenic Escherichia coli / drug effects
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Uropathogenic Escherichia coli / enzymology
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Uropathogenic Escherichia coli / isolation & purification
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Urothelium / cytology
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Virulence Factors / antagonists & inhibitors
Substances
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4-(5-nitroindolin-1-yl)phenyl mannopyranoside
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Adhesins, Escherichia coli
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Anti-Infective Agents, Urinary
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Benzene Derivatives
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Indoles
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Mannosides
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Virulence Factors
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fimH protein, E coli
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Fimbriae Proteins