Mannoside Compounds Inhibit FimH Adhesion to Prevent UTI Recurrence
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Solution Overview
Problem
Current treatments for urinary tract infections (UTIs) and inflammatory bowel disease (IBD) are inadequate in preventing recurrence and addressing the quiescent intracellular reservoirs that contribute to recurrent UTIs, and there is a need for effective therapies that can reduce symptoms associated with Crohn's disease.
Innovation Solution
Development of compounds that inhibit the FimH adhesin protein, specifically designed to prevent bacterial colonization and invasion by blocking the mannose binding site, thereby reducing bacterial amplification and formation of biofilms in the bladder and gut, which are formulated into pharmaceutical compositions for administration to treat and prevent UTIs and IBD.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotic therapy is used to treat UTIs, then bacterial clearance from urine is achieved, but recurrence of infection occurs due to quiescent intracellular reservoirs
Solution Approach 1:
The mannoside compounds are administered to prevent bacterial adhesion to bladder epithelium before infection can establish quiescent intracellular reservoirs. By blocking FimH-mediated attachment, the treatment preemptively stops the pathogenic cascade that leads to recurrent infections, addressing the recurrence problem before it manifests.
Solution Approach 2:
Mannoside compounds act as intermediary molecules that compete with host ligands for binding to bacterial FimH adhesin. These synthetic mannose derivatives serve as decoy receptors, intercepting the bacterial adhesion process and preventing bacteria from attaching to bladder epithelial cells, thereby eliminating the reservoir formation without requiring direct antibiotic action on intracellular bacteria.
2Reliability
If FimH adhesin is blocked to prevent bacterial colonization, then UTI recurrence is reduced, but bacterial amplification and biofilm formation in bladder and gut must be inhibited simultaneously
Solution Approach 1:
The mannoside compounds exhibit universal anti-adhesive activity against FimH-expressing bacteria in multiple anatomical sites including the bladder and gut. A single compound class addresses colonization prevention, bacterial amplification inhibition, and biofilm formation blockade across different physiological environments, simplifying the treatment approach despite the multifaceted pathogenic process.
3Reliability
If mannose binding site is blocked to prevent adhesion, then bacterial invasion into bladder epithelium is prevented, but effective delivery to target site is required
Solution Approach 1:
The mannoside compounds leverage the bacteria's own adhesion mechanism against them. The compounds' mannose moieties specifically bind to FimH with high affinity, and their pharmacokinetic properties enable them to reach the urinary tract and gastrointestinal tract where they self-administer by competing for bacterial binding sites. The compounds' structural design ensures they remain stable and active in physiological conditions, enabling effective delivery without complex administration systems.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively reduce bacterial titers in the bladder and gut, preventing recurrence of UTIs and alleviating symptoms of IBD by inhibiting FimH-mediated adhesion and biofilm formation, demonstrating improved efficacy over existing treatments.
Implementation Method 1
The mannose binding FimH adhesin of type 1 pili is critical for the colonization and invasion into the bladder epithelium. The X-ray crystal structure of FimH bound to mannose showed that mannose is bound in a negatively charged pocket on FimH.
Implementation Method 2
The compounds effectively reduce bacterial titers in the bladder and gut, preventing recurrence of UTIs and alleviating symptoms of IBD by inhibiting FimH-mediated adhesion and biofilm formation
Data Source
Figure 1~1C
Figure 1D
Figure 2~2C
AI summary
The present invention encompasses compounds and methods for treating and preventing bacterial infections specifically urinary tract infections and those caused by bacteria containing type 1 pili and FimH. The present invention also encompasses compounds and methods for treating inflammatory bowel disease specifically Crohn's Disease.