Chimeric Ectolysins for Selective Staphylococcal Lysis
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Solution Overview
Problem
Existing chimeric polypeptides lack the ability to selectively suppress the growth of certain bacterial species within the Staphylococci genus, such as S. aureus and S. hominis, without affecting closely related species like S. epidermidis, which are beneficial to the skin microbiome.
Innovation Solution
Development of chimeric polypeptides comprising the CHAP domain and Sh3b domain from lysostaphin, with specific amino acid sequences (SEQ ID NO:2, 6, or 8) that selectively target and suppress S. aureus and/or S. hominis while sparing S. epidermidis, formulated for topical application.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing chimeric polypeptides are used to suppress bacterial growth, then anti-staphylococcal activity is achieved, but selectivity between pathogenic and beneficial species is lost
Solution Approach 1:
The patent applies local quality by modifying specific amino acid residues within the CHAP domain of the chimeric polypeptide to create localized changes in binding affinity and catalytic efficiency. These targeted modifications at specific positions enable the protein to distinguish between pathogenic and beneficial staphylococcal species, achieving selectivity without losing overall anti-staphylococcal activity.
Solution Approach 2:
The patent employs parameter changes by systematically varying amino acid sequences, particularly in the CHAP domain, to alter the biochemical parameters of the chimeric polypeptide. These changes in primary structure result in modified substrate specificity and catalytic rates, enabling selective suppression of pathogenic species while sparing beneficial commensals.
2Productivity
If broad-spectrum anti-staphylococcal proteins are used, then diverse Staphylococcus species are killed, but beneficial skin flora are eliminated
Solution Approach 1:
The patent applies segmentation by dividing the Staphylococcus genus into target and non-target groups based on species-specific characteristics. The chimeric polypeptide is engineered to segment its activity accordingly, maintaining high killing efficiency against pathogenic species while selectively ignoring beneficial species through optimized binding and catalytic properties.
Solution Approach 2:
The patent converts the potential harm of broad-spectrum activity into benefit by designing the chimeric polypeptide to exploit species-specific differences in cell wall composition and structure. The high killing efficiency against pathogens is maintained while the same properties are tuned to avoid affecting beneficial species, thus converting what would be harmful non-selectivity into beneficial selectivity.
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 polypeptides effectively suppress the growth of targeted Staphylococci species without significantly impacting non-targeted species, maintaining the balance of the skin microbiome and preventing dysbiosis.
Implementation Method 1
The chimeric protein termed P128... harbor the catalytic Cysteine Histidine-dependent aminohydrolase/peptidase (CHAP) domain
Implementation Method 2
catalytic Cysteine Histidine-dependent aminohydrolase/peptidase (CHAP) domain and the targeting Sh3b domain from lysostaphin
Implementation Method 3
the targeting Sh3b domain from lysostaphin... provides target bacterial cell binding activity
Data Source
AI summary
The present invention provides chimeric ectolysins useful for selective suppression of certain targeted bacterial species while having little to no effect on closely related non-targeted bacterial species. Specifically, the disclosure provides polypeptides for selective suppression of growth of Staphylococcus aureus and/or S. hominis but not S. epidermidis. Compositions and methods for selective suppression of target bacterial species are also provided.