FimH antagonists: structure-activity and structure-property relationships for biphenyl α-D-mannopyranosides

Area of Science:

• Microbiology
• Pharmacology
• Biochemistry

Background:

• Urinary tract infections (UTIs) are commonly caused by uropathogenic Escherichia coli (UPEC).
• UPEC utilizes type 1 pili, with FimH adhesin at the tip, to bind to host urothelial cells via mannose residues.
• Current FimH antagonists often have suboptimal pharmacokinetics and variable binding modes, limiting clinical application.

Purpose of the Study:

• To design and synthesize novel biphenyl α-D-mannoside derivatives as FimH antagonists.
• To enhance binding affinity and optimize pharmacokinetic properties of FimH antagonists.
• To elucidate the binding mode of these antagonists to the FimH carbohydrate recognition domain (CRD).

Main Methods:

• Synthesis of biphenyl α-D-mannoside derivatives.
• Inhibition assays: cell-free competitive binding, cell-based flow cytometry.
• Isothermal titration calorimetry (ITC) to determine binding thermodynamics.
• Pharmacokinetic analysis including log D, solubility, and membrane permeation.

Main Results:

• Established structure-activity relationships (SAR) for biphenyl α-D-mannosides targeting FimH.
• Identified derivatives with improved binding affinity and favorable pharmacokinetic profiles.
• Characterized the binding modes of the antagonists to the FimH CRD.

Conclusions:

• Biphenyl α-D-mannosides represent a promising class of compounds for UTI prevention and treatment.
• Optimized derivatives offer potential for clinical development due to enhanced efficacy and drug-like properties.
• Understanding SAR and binding modes guides the rational design of future FimH antagonists.