Chimeric Cell Wall Hydrolases for Selective S. Aureus Lysis
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Solution Overview
Problem
Current therapeutic tools for Staphylococcus infections, such as antibiotics and chemicals like benzoyl peroxide, are ineffective against antibiotic-resistant strains and negatively impact the skin microbiome, leading to unmet needs for precise treatments.
Innovation Solution
Development of novel chimeric cell wall hydrolases (CWHs) with specific enzymatically active domains (EADs) and cell wall binding domains (CBDs) that selectively target and lyse Staphylococcus aureus, preserving commensal bacteria.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotics or chemicals like benzoyl peroxide are used to treat bacterial infections, then pathogenic Staphylococcus strains can be targeted, but commensal bacterial populations are negatively affected
Solution Approach 1:
The cell wall hydrolase is divided into separate functional domains: a cell wall binding domain (CBD) that provides species-specific targeting, and an enzymatically active domain (EAD) that performs the lytic function. This segmentation allows the CBD to selectively bind to S. aureus cell wall components while the EAD executes the killing action, preventing off-target effects on commensal bacteria.
Solution Approach 2:
The CBD is engineered with specific local properties that enable selective binding to S. aureus cell wall peptidoglycan structures. This localized specificity ensures that the enzymatic activity is concentrated only at the target pathogen site, leaving commensal bacterial populations unaffected.
2Reliability
If broad-spectrum antibiotics are used to treat Staphylococcus infections, then antibiotic-resistant strains become more difficult to manage, but the need for new therapeutic approaches increases
Solution Approach 1:
The patent replaces the chemical mechanism of antibiotics with a mechanical/enzymatic mechanism. Cell wall hydrolases physically degrade the peptidoglycan cell wall structure through enzymatic hydrolysis, a mechanism fundamentally different from antibiotic targets. This substitution reduces the likelihood of resistance development since the cell wall degradation mechanism is harder for bacteria to evade.
Solution Approach 2:
The chimeric CWH combines two different protein domains (CBD and EAD) into a single functional molecule. This composite structure integrates targeting specificity with enzymatic activity, creating a therapeutic agent that operates through a novel mechanism distinct from conventional antibiotics, thereby addressing resistance issues.
3Object-affected harmful factors
If chimeric cell wall hydrolases are designed with high specificity for S. aureus, then selective treatment is achieved, but the complexity of domain engineering increases
Solution Approach 1:
The CBD serves multiple functions: it provides species-specific binding affinity, directs the enzyme to the target cell wall, and ensures proper orientation of the EAD for optimal catalytic activity. This multi-functionality reduces the need for additional separate targeting molecules, simplifying the overall design despite the chimeric nature of the protein.
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 chimeric CWHs demonstrate high lytic activity against Staphylococcus aureus while minimizing impact on healthy bacteria, effectively treating conditions like atopic dermatitis and acute radiation dermatitis.
Implementation Method 1
a cell wall binding domain (CBD) having at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identity with the sequence of: i) SEQ ID NO: 16; ii) SEQ ID NO: 17; or iii) SEQ ID NO: 18
Implementation Method 2
an enzymatically active domain (EAD) having at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identity with SEQ ID NO: 11
Implementation Method 3
chimeric cell wall hydrolases (CWHs) that selectively target and lyse Staphylococcus aureus
Data Source
AI summary
The present disclosure relates to novel chimeric cell wall hydrolases with anti-Staphylococcus activity. The disclosure also relates to compositions comprising these chimeric cell wall hydrolases and uses thereof in the treatment of conditions associated with Staphylococcus sp.