FimH Lectin-Domain Mutants for Blocking E. coli Adhesion
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Solution Overview
Problem
Current vaccines targeting FimH adhesin protein from E. coli are ineffective in preventing urinary tract infections (UTIs) due to the high-affinity conformation of the FimH lectin domain, which promotes bacterial adhesion, and existing FimH mutants fail to induce highly inhibitory antibodies.
Innovation Solution
A polypeptide with a FimH lectin domain mutated at position 144 to low-affinity conformation, such as F144V, is developed to induce antibodies that inhibit mannose-mediated adhesion, combined with FimC to form a FimCH complex, and formulated with adjuvants for immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type FimH adhesin is used as vaccine, then high levels of antibodies are induced, but the antibodies fail to inhibit bacterial adhesion due to the high-affinity conformation promoting adhesion
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues (e.g., Q133K, R60P, F144V) in the FimH lectin domain to alter its conformational equilibrium, shifting it from high-affinity to low-affinity state for mannose binding. This parameter change in the protein structure enables the induced antibodies to effectively inhibit bacterial adhesion while maintaining immunogenicity.
2Object-generated harmful factors
If FimH mutants with low-affinity conformation are used, then antibody-mediated inhibition of adhesion is improved, but the mutants may have reduced immunogenicity or stability
Solution Approach 1:
The patent introduces additional amino acid mutations beyond the single residue change, such as combining Q133K with R60P or F144V mutations. These multiple mutations work together to stabilize the low-affinity conformation and enhance adhesion inhibition while maintaining sufficient immunogenicity for effective vaccine response.
Solution Approach 2:
The patent creates composite mutant structures by combining multiple amino acid substitutions within the FimH lectin domain. These composite mutations (e.g., Q133K_R60P, Q133K_F144V) generate a synergistic effect that stabilizes the desired low-affinity conformation while preserving overall protein structure and immunogenic properties.
Data Source
AI summary
Polypeptides comprising a FimH lectin domain comprising an amino acid mutation that causes the FimH lectin domain to be in the low affinity conformation for mannose are described. Pharmaceutical compositions which comprise such polypeptides and methods of stimulating an immune response in a subject in need thereof by administration of the polypeptide are further described.