Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections
Laurel Mydock-McGrane1, Zachary Cusumano1, Zhenfu Han
1Fimbrion Therapeutics, Inc. , Saint Louis, Missouri 63108 United States.
Abstract:
Gram-negative uropathogenic Escherichia coli (UPEC) bacteria are a causative pathogen of urinary tract infections (UTIs). Previously developed antivirulence inhibitors of the type 1 pilus adhesin, FimH, demonstrated oral activity in animal models of UTI but were found to have limited compound exposure due to the metabolic instability of the O-glycosidic bond (O-mannosides). Herein, we disclose that compounds having the O-glycosidic bond replaced with carbon linkages had improved stability and inhibitory activity against FimH. We report on the design, synthesis, and in vivo evaluation of this promising new class of carbon-linked C-mannosides that show improved pharmacokinetic (PK) properties relative to O-mannosides. Interestingly, we found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. This new class of C-mannoside antagonists have significantly increased compound exposure and, as a result, enhanced efficacy in mouse models of acute and chronic UTI.
Insights
Researchers developed new C-mannoside drugs that are more stable and effective against urinary tract infections (UTIs) caused by E. coli. These antivirulence inhibitors show improved pharmacokinetics and enhanced efficacy in treating UTIs.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Pharmacology
Background:
- Gram-negative uropathogenic Escherichia coli (UPEC) cause urinary tract infections (UTIs).
- Previous FimH inhibitors (O-mannosides) had limited efficacy due to metabolic instability.
- The O-glycosidic bond in O-mannosides is metabolically unstable, limiting compound exposure.
Purpose of the Study:
- To design and synthesize novel carbon-linked C-mannosides as antivirulence inhibitors of FimH.
- To evaluate the stability, pharmacokinetic properties, and in vivo efficacy of C-mannosides in UTI models.
Main Methods:
- Chemical synthesis of carbon-linked C-mannosides.
- In vitro assessment of FimH inhibitory activity.
- In vivo evaluation in mouse models of acute and chronic UTI.
- Pharmacokinetic studies to assess compound exposure.
Main Results:
- Carbon-linked C-mannosides exhibit improved metabolic stability compared to O-mannosides.
- FimH binding is stereospecifically influenced by hydroxyl substitution on the linker.
- The R-hydroxy isomer demonstrated a 60-fold increase in potency.
- Enhanced compound exposure and improved efficacy in mouse UTI models were observed.
Conclusions:
- Carbon-linked C-mannosides represent a promising new class of antivirulence agents against UPEC.
- These compounds offer improved pharmacokinetic properties and enhanced efficacy for UTI treatment.
- The stereospecific modulation of FimH binding provides a basis for further drug optimization.
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