Modified Cathelicidin Peptides for Gram-Negative Bacteria

Solution Overview

Problem

Current antimicrobial peptides, such as cathelicidins, face challenges due to high cytotoxicity and pro-inflammatory effects, which limit their use in treating bacterial infections, especially against Gram-negative bacteria, and the emergence of antibiotic-resistant strains necessitates the development of novel antimicrobials.

Innovation Solution

Modified peptides derived from native cathelicidins with clustered positively charged basic residues and limited acidic residues are designed to reduce cytotoxicity and pro-inflammatory effects, enhancing direct killing of Gram-negative bacteria while allowing for reduced antibiotic dosages, even in antibiotic-resistant cases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If native cathelicidin peptides are used to kill bacteria, then direct killing activity is achieved, but cytotoxicity and pro-inflammatory effects increase

Engineering Contradiction:

Improvebactericidal activityVSAvoidcytotoxicity and pro-inflammatory effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by concentrating positively charged basic residues specifically within the N-terminal sequence of the peptide, while limiting acidic residues throughout the entire sequence. This localized modification of charge distribution enhances bactericidal activity against Gram-negative bacteria while reducing cytotoxicity and pro-inflammatory effects, as the positive charge cluster targets bacterial membranes without triggering excessive inflammatory responses in mammalian cells.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the chemical parameters of the peptide by modifying the amino acid sequence to have at least 30% clustered basic residues in the N-terminal region and no more than 10% acidic residues overall. This parameter change in charge composition fundamentally alters the peptide's interaction properties, enabling selective killing of bacteria while sparing mammalian cells from cytotoxic damage.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If higher dosages of antibiotics are used to treat antibiotic-resistant bacteria, then bacterial killing efficacy is improved, but side effects and toxicity increase

Engineering Contradiction:

Improvebacterial killing efficacyVSAvoidside effects and toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces modified cathelicidin peptides as intermediary agents that work synergistically with antibiotics. These peptides disrupt bacterial membranes and interfere with bacterial defense mechanisms, thereby enhancing the effectiveness of lower antibiotic dosages. This intermediary action allows treatment of antibiotic-resistant bacteria while avoiding the high doses of antibiotics that would cause severe side effects and toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If native cathelicidin sequences are used, then broad antimicrobial coverage is achieved, but pro-inflammatory autoimmune effects occur

Engineering Contradiction:

Improveantimicrobial coverageVSAvoidpro-inflammatory autoimmune effects

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by concentrating positively charged basic residues specifically within the N-terminal sequence of the peptide, while limiting acidic residues throughout the entire sequence. This localized modification of charge distribution enhances bactericidal activity against Gram-negative bacteria while reducing cytotoxicity and pro-inflammatory effects, as the positive charge cluster targets bacterial membranes without triggering excessive inflammatory responses in mammalian cells.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS10435447B2Bacteriocidal peptides and uses thereof

Publication Date: 2019.10.08 INDIANA UNIVERSITY RESEARCH & TECHNOLOGY CORP

AI summary

Peptide compositions having bacteriocidal peptides are described. Also described is a method of bacterial infections using compositions comprising bacteriocidal peptides or modified peptides with structural relationships to cathelicidins.