Chimeric Endolysin Merging M23 and CHAP Domains for Staphylococcus Lysis
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Solution Overview
Problem
There is a high demand for novel drugs effective against antibiotic-resistant Staphylococcus infections, particularly for systemic infections and sepsis, as existing treatments face challenges due to high antibiotic resistance and physically restricted access to infection sites.
Innovation Solution
A chimeric endolysin polypeptide combining an M23 endopeptidase and a CHAP domain provides enhanced lytic activity and stability against both coagulase-positive and coagulase-negative Staphylococcus species, such as S. aureus and S. epidermidis, with at least 90% sequence identity to specific amino acid sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a single endolysin with CHAP domain is used, then the structure is simple and easy to produce, but the lytic activity and stability against Staphylococcus species is insufficient
Solution Approach 1:
The patent combines two different enzymatic domains (M23 endopeptidase and CHAP domain) into a single chimeric endolysin polypeptide. This merging allows the molecule to possess both cleavage activities simultaneously, enhancing its ability to degrade peptidoglycan in Staphylococcus cell walls while maintaining a single-producer system that is easier to manufacture than multiple separate enzymes.
Solution Approach 2:
The chimeric endolysin is constructed as a composite protein molecule containing two distinct functional domains (M23 and CHAP) with different catalytic mechanisms. This composite structure enables the single polypeptide to exhibit enhanced and complementary lytic activities against Staphylococcus species that neither domain could achieve alone, while remaining producible as a single recombinant protein.
2Reliability
If separate PGHs are used in combination, then the lytic activity is enhanced, but the device complexity and administration difficulty increase
Solution Approach 1:
The patent merges two separate peptidoglycan hydrolase functions (M23 endopeptidase activity and CHAP domain activity) into a single chimeric polypeptide molecule. This eliminates the need to administer, stabilize, and coordinate multiple separate enzymes, simplifying the therapeutic formulation and administration process while maintaining the enhanced lytic activity that results from having both cleavage mechanisms present.
3Reliability
If antibiotics are used, then the treatment is established and effective against sensitive bacteria, but antibiotic resistance develops and reduces effectiveness
Solution Approach 1:
The patent replaces the chemical inhibition mechanism of antibiotics with a mechanical/enzymatic degradation mechanism. Instead of blocking bacterial growth through chemical interference with metabolic pathways (which bacteria can resist through modification of target sites), the chimeric endolysin directly cleaves and degrades the peptidoglycan structural component of the cell wall through two different enzymatic activities, a mechanism to which bacteria have not developed resistance.
Solution Approach 2:
The patent exploits the essential structural role of peptidoglycan in bacterial cell walls - a target that is fundamental to bacterial survival and cannot be modified without destroying the cell wall itself. By targeting this essential structural component with two different cleavage mechanisms, the invention converts the bacteria's reliance on rigid cell wall structure into vulnerability, as the very feature that provides structural integrity becomes the target of degradation.
4Device complexity
If a single cleavage site PGH is used, then the enzyme is simple to design, but the accessibility to different bonds in the three-dimensional PG network is limited
Solution Approach 1:
The patent merges two different cleavage capabilities (M23 endopeptidase cleaving the pentaglycine cross-bridge and CHAP domain cleaving the stem peptide-peptide bridge linkage) into a single polypeptide. This allows one enzyme molecule to attack the peptidoglycan network at two different bond types, increasing accessibility to the three-dimensional PG structure without requiring multiple separate enzymes, thereby maintaining relative simplicity while enhancing effectiveness.
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 endolysin polypeptide demonstrates improved antimicrobial activity and stability in human serum, offering potential therapeutic benefits for treating Staphylococcus infections, including conditions like bacteraemia, infective endocarditis, and prosthetic joint infections.
Implementation Method 1
The M23 domains of LST and ALE1 cleave the pentaglycine cross-bridge, which connects adjacent stem peptides in the PG of S. aureus
Implementation Method 2
Depending on the CHAP domain present, cleavage can occur at different locations in the PG, including the amide bond of the sugar backbone to the stem peptide
Implementation Method 3
Peptidoglycan hydrolases (PGHs) can cleave specific bonds within the peptidoglycan (PG) network of bacteria and have been shown to be active against biofilms
Data Source
Figure 1
Figure 2A~2B
Figure 2C~2D
AI summary
The invention relates to the field of medicine, specifically to the field of treatment of conditions associated with Staphylococcus infection. The invention relates to a novel endolysin polypeptide specifically targeting a bacterial Staphylococcus cell. The invention further relates to said endolysin polypeptide for medical use, preferably for treating an individual suffering from a condition associated with Staphylococcus infection.