Chimeric Cell Wall Hydrolases for Soluble C. Acnes Lysis
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Solution Overview
Problem
Current endolysins targeting Cutibacterium acnes face challenges due to low diversity, low solubility, and low activity, limiting their effectiveness in treating acne and maintaining skin microbiome balance.
Innovation Solution
Development of chimeric cell wall hydrolases (CWHs) comprising a CW_7 cell wall binding domain (CBD) and a CLC1-family enzymatically active domain (EAD) with enhanced specificity and activity against Cutibacterium acnes, including recombinant proteins and formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If endolysins targeting C. acnes are developed, then lytic activity against C. acnes is improved, but solubility and stability are worsened
Solution Approach 1:
The endolysin is divided into separate functional domains (cell wall binding domain and catalytic domain) that can be independently optimized. The CBD targets C. acnes specifically while the EAD provides lytic activity, allowing each domain to be engineered for optimal performance without compromising the other's stability or solubility characteristics.
Solution Approach 2:
The patent creates chimeric proteins combining endolysin domains with other protein structures or modifications to improve solubility and stability. These composite structures maintain the core lytic function while adding properties that enhance manufacturability and therapeutic potential.
2Measurement precision
If endolysins targeting C. acnes are developed, then species-specificity is improved, but diversity of available endolysins is worsened
Solution Approach 1:
By separating the species-specific binding function (CBD) from the catalytic function (EAD), the patent enables independent optimization and combination of different domains. This allows creation of diverse chimeric endolysins with tailored specificities for different C. acnes strains while maintaining robust catalytic activity.
Solution Approach 2:
The patent develops a platform where a single catalytic domain can be paired with multiple different binding domains to target various C. acnes phylotypes. This multi-functional approach expands the diversity of available therapies without requiring complete redesign of the catalytic mechanism for each strain.
3Reliability
If chimeric cell wall hydrolases are developed with enhanced activity, then lytic activity against C. acnes is improved, but device complexity is worsened
Solution Approach 1:
The chimeric hydrolases are constructed from modular domains that can be systematically assembled. This segmentation allows rational design and simplifies the complexity by breaking down the protein structure into predictable, interchangeable units with defined functions.
Solution Approach 2:
The patent optimizes specific parameters of the chimeric proteins (domain composition, linkers, fusion partners) to enhance lytic activity while maintaining manufacturability. By systematically varying these parameters, the patent identifies configurations that balance enhanced activity with acceptable structural complexity.
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 CWHs demonstrate significantly increased lytic activity and species-specificity against Cutibacterium acnes, restoring phylotype diversity and reducing acne-related inflammation without affecting commensal bacteria.
Implementation Method 1
chimeric cell wall hydrolases (CWHs) comprising a CW_7 cell wall binding domain (CBD) and a CLC1-family enzymatically active domain (EAD) with enhanced specificity and activity against Cutibacterium acnes
Implementation Method 2
Endolysins are phage-encoded bacterial cell wall-degrading enzymes that catalyze rapid and selective killing of bacteria
Implementation Method 3
The endolysin binds and rapidly degrades the host bacterium cell wall, causing the cell to burst
Data Source
AI summary
The present disclosure relates to novel cell wall binding domains, enzymatically active domains, and chimeric cell wall hydrolases with anti-Cutibacterium acnes activity. The disclosure also relates to compositions comprising these, and uses thereof in the treatment of conditions associated with Cutibacterium acnes.