Antimicrobial Peptides With Metal-Binding Motifs

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Solution Overview

Problem

The rise of antibiotic-resistant bacteria, particularly carbapenem-resistant Enterobacteriaceae, and the formation of biofilms on medical devices pose a significant challenge due to the limited efficacy of standard antibiotics and the lack of approved anti-biofilm drugs, leading to chronic and refractory infections with high treatment costs and mortality.

Innovation Solution

Development of antimicrobial peptides with an amino-terminal Cu(II) and Ni(II) binding motif, such as the ATCUN motif, conjugated to the N-terminus of existing peptides to enhance their antimicrobial activity, which generates reactive oxygen species and degrades extracellular DNA within biofilms, thereby disrupting biofilm formation and increasing susceptibility to conventional antibiotics.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If standard antibiotics are used to treat bacterial infections, then bacterial growth is inhibited, but antibiotic resistance develops and efficacy is limited

Engineering Contradiction:

Improveantibiotic efficacyVSAvoidantibiotic resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical structure of antimicrobial peptides by incorporating metal-binding motifs (GGH, VIH, HRH) at the N-terminus, changing the peptide's binding parameters to metal ions (Cu2+, Ni2+) to enhance antimicrobial activity and overcome resistance mechanisms of standard antibiotics

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite antimicrobial agents by combining peptide sequences with metal-binding capabilities, forming a hybrid system that integrates the peptide portion with metal ion coordination chemistry to achieve enhanced antimicrobial and antibiofilm activity

Inventive Principle:

Principle #40Composite materials

2Reliability

If naturally occurring antimicrobial peptides are used, then antimicrobial activity is achieved, but cytotoxicity and insufficient activity are problems

Engineering Contradiction:

Improveantimicrobial activityVSAvoidcytotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces metal-binding motifs specifically at the N-terminus of the peptide, localizing the metal coordination function to a specific region while maintaining the peptide's overall structure and reducing cytotoxic effects through targeted modification

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

By modifying the N-terminal amino acid sequence to include metal-binding motifs, the patent changes the peptide's binding affinity and metal ion coordination parameters to enhance antimicrobial activity while maintaining biocompatibility

Inventive Principle:

Principle #35Parameter changes

3Reliability

If biofilms are formed by bacteria, then protection from exogenous agents is achieved, but treatment becomes refractory and chronic infections occur

Engineering Contradiction:

Improvebiofilm protectionVSAvoidtreatment efficacy

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The metal-binding motifs in the peptides act as intermediaries that chelate metal ions (Cu2+, Ni2+) to generate reactive oxygen species, which serve as the active killing agents that penetrate and disrupt the biofilm protective matrix

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The peptides utilize metal ion chelation to generate reactive oxygen species through oxidation reactions, creating strong oxidative stress that degrades biofilm extracellular polymeric substances and kills embedded bacteria, overcoming the protective barrier

Inventive Principle:

Principle #38Strong oxidants (Accelerated oxidation)

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 modified peptides demonstrate enhanced antimicrobial activity against resistant bacteria, including carbapenem-resistant strains, with reduced hemolytic toxicity and improved survival rates in animal models, offering a potential alternative to traditional antibiotics and naturally occurring antimicrobial peptides.

Implementation Method 1

an amino-terminal Cu(II) and Ni(II) binding motif that is conjugated to the N-terminus of the peptide portion

Methodology Applied

Scientific EffectMetal ion coordination:

Implementation Method 2

generates reactive oxygen species and degrades extracellular DNA within biofilms

Methodology Applied

Scientific EffectReactive oxygen species generation:

Implementation Method 3

degrades extracellular DNA within biofilms, thereby disrupting biofilm formation

Methodology Applied

Scientific EffectDNA degradation:

Data Source

PatentUS20220064219A1Antimicrobial And Antibiofilm Peptides Sequences With Metal-Binding Motifs

Publication Date: 2022.03.03 THE TRUSTEES OF THE UNIV OF PENNSYLVANIA

AI summary

Provided herein are synthetic peptides with enhanced antimicrobial and antibiofilm characteristics, and are biocompatible with mammalian cellular systems. The disclosed synthetic antimicrobial moieties include a peptide portion and an amino-terminal Cu(II) and Ni(II) binding motif that is conjugated to the N-terminus of the peptide portion. Also provided are compositions comprising the synthetic peptides, as well as methods of treating a microbial infection or removing a biofilm using the peptides.