Substituted Biphenyl or Phenylheteroaryl Mannosides for FimH Blocking
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Solution Overview
Problem
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are prevalent and often recurrent, with increasing antibiotic resistance, and there is a need for new therapies that can inhibit the FimH adhesin to prevent bacterial colonization and invasion of bladder epithelium.
Innovation Solution
Development of novel O-mannoside compounds that inhibit FimH activity, targeting the mannose-binding site to disrupt the interaction between FimH and host proteins, thereby preventing bacterial colonization and invasion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotics are used to treat UTI, then bacterial infection is reduced, but antibiotic resistance develops
Solution Approach 1:
The patent uses mannose and its derivatives as intermediary molecules that bind to the FimH adhesin on bacterial surfaces, preventing the adhesin from binding to host bladder epithelium. This competitive inhibition strategy interrupts the infection mechanism without using antibiotics, thereby avoiding the development of antibiotic resistance while still effectively treating UTI
Solution Approach 2:
The patent modifies the basic mannose structure by introducing various substituents (fluorine atoms, hydroxyl groups, sugar moieties) to create derivatives with optimized binding affinity to FimH. These structural parameter changes enhance the inhibitory effectiveness against FimH-mediated bacterial adhesion while maintaining the non-antibiotic mechanism of action
2Reliability
If FimH activity is inhibited to prevent bacterial colonization, then UTI and related diseases are treated, but new therapeutic agents are required due to existing treatment limitations
Solution Approach 1:
The patent segments the complex FimH adhesin molecule into its critical binding pocket region, which specifically recognizes mannose structures. By focusing on this segmented target site, the invention designs mannose derivatives that selectively bind to this specific region, enabling effective inhibition of FimH function without needing to develop entirely new complex therapeutic agents
Solution Approach 2:
The patent creates synthetic copies of mannose molecules (mannose derivatives) that replicate and enhance the natural binding interaction between mannose and FimH. These copied structures are optimized to bind more effectively to the FimH binding pocket, providing therapeutic effect through a simplified approach that avoids the complexity of developing novel non-mannose based therapies
Data Source
AI summary
Disclosed herein are new O-biphenyl- and O-phenylheteroarylmannoside compounds and compositions and their application as pharmaceuticals for use in the treatment of human disease. Methods of inhibition of FimH activity in human subjects are also provided for the treatment of diseases such as urinary tract infection.