Chimeric Endolysins for Staphylococcus Lysis and Stability
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Solution Overview
Problem
Current strategies for treating Staphylococcal infections, including antibiotic therapy and antimicrobial peptides, face challenges such as rising antibiotic resistance, high development costs, and immune response issues with phage therapy, necessitating the development of more effective and resistant-targeting endolysins for Staphylococcus species.
Innovation Solution
The development of a polypeptide variant, ply_pitti26, and its derivatives with enhanced activity and stability, combining CHAP and amidase domains with cell-binding domains from various endolysins, to create chimeric endolysins that effectively lyse Staphylococcus bacteria, including MRSA strains, with improved solubility, stability, and host range recognition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard antibiotic therapy is used to treat Staphylococcal infections, then infections can be controlled, but antibiotic resistance develops making therapy ineffective
Solution Approach 1:
The patent extracts and utilizes the endolysin enzyme from bacteriophages, separating this lytic function from the complete phage system. This extracted endolysin can directly target and degrade bacterial cell walls without requiring phage replication, thereby avoiding the development of antibiotic resistance while maintaining therapeutic effectiveness against Staphylococcus infections
Solution Approach 2:
The patent employs endolysin as an intermediary substance that mediates between the therapeutic goal (killing bacteria) and the problem of resistance. The endolysin acts as a direct cell wall-degrading enzyme that bypasses traditional antibiotic targets, providing an alternative mechanism that does not contribute to resistance development
2Adaptability or versatility
If phage therapy is used to treat bacterial infections, then antibiotic resistance is avoided, but immune response and tissue penetration problems occur
Solution Approach 1:
The patent extracts only the essential endolysin enzymatic component from the complete bacteriophage system. This extracted endolysin retains the ability to degrade bacterial cell walls and avoid antibiotic resistance while eliminating the problematic aspects of whole phage therapy, including immune response issues and tissue penetration barriers
Solution Approach 2:
The patent creates a simplified copy of the phage's therapeutic function by producing the endolysin enzyme separately through recombinant expression systems. This copied enzymatic function achieves the desired antibacterial effect without requiring the complex phage structure, thereby avoiding immune recognition and tissue penetration problems
3Reliability
If endolysins are used to kill bacteria, then bacterial cell walls are hydrolyzed, but solubility and stability improvements are needed for therapeutic use
Solution Approach 1:
The patent applies parameter changes to the endolysin protein structure through site-directed mutagenesis, specifically modifying amino acid residues to enhance solubility and thermal stability. These parameter changes maintain the enzyme's lytic activity while improving its composition stability for therapeutic applications
Solution Approach 2:
The patent applies local quality modifications by making specific targeted changes to particular regions of the endolysin molecule. By modifying specific amino acid residues rather than the entire protein structure, the patent locally improves solubility and stability properties while preserving the overall catalytic function and bacterial cell wall hydrolysis activity
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 endolysins demonstrate superior lysis activity and stability, effectively targeting Staphylococcus species, including MRSA, with enhanced solubility and thermal stability, offering a promising therapeutic and prophylactic solution for Staphylococcal infections.
Implementation Method 1
Endolysins enzymatically hydrolyse the cell walls of those bacteria which are host organisms for their corresponding bacteriophages
Data Source
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Figure 3A~3B
AI summary
The present invention relates to a polypeptide termed ply_pitti26 comprising the sequence as depicted in SEQ ID NO: 1 as well as variants of this polypeptide. Furthermore, the present invention relates to nucleic acids and vectors encoding for said polypeptide and variants thereof as well as host cells comprising these nucleic acids and/or vectors. Finally, the present invention relates to the uses of said polypeptide, variants thereof, nucleic acid sequences, vectors and host cells, in particular for the treatment or prophylaxis of a subject infected by or exposed to Staphylococci.