Backbone-Cyclized Peptide Combinations for Antibiotic Resistance
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Solution Overview
Problem
Current antibiotics face challenges with microbial resistance, particularly against pathogens like Pseudomonas aeruginosa, and existing combination therapies lack predictive power for in vivo efficacy, necessitating the development of novel antimicrobial agents with new modes of action.
Innovation Solution
A combination of a β-hairpin peptidomimetic compound, cyclo(-Thr-Trp-Ile-Dab-Orn-Dab-Dab-Trp-Dab-Dab-Ala-Ser- Pro-Pro), with antibiotics such as ertapenem, azithromycin, ciprofloxacin, or amikacin, which allows for therapeutic control of bacterial infections at lower doses and synergistic action against a wide range of bacteria, including Pseudomonas aeruginosa.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibiotics are used to treat bacterial infections, then antimicrobial activity is achieved, but microbial resistance develops and efficacy decreases
Solution Approach 1:
The patent divides the antimicrobial therapy into two segments: a backbone-cyclized peptide providing structural stability and membrane targeting, and a small molecule antibiotic providing enzymatic inhibition. This segmentation allows each component to target different resistance mechanisms, with the peptide preventing efflux pump activity and the small molecule inhibiting cell wall synthesis, thereby reducing overall microbial resistance development.
Solution Approach 2:
The invention creates a composite therapeutic system combining a backbone-cyclized peptide (providing structural framework and membrane interaction) with a small molecule antibiotic (providing biochemical inhibition). This composite approach leverages the complementary mechanisms of both components to achieve synergistic antimicrobial activity while circumventing resistance pathways that affect single agents.
2Reliability
If combination therapies are developed to overcome resistance, then antimicrobial efficacy is improved, but predictive power for in vivo efficacy is lacking
Solution Approach 1:
The patent performs preliminary in silico modeling and in vitro characterization before in vivo application, establishing predictive relationships between combination components and their synergistic effects. By pre-determining the mechanistic interactions and dose relationships through controlled experiments, the invention creates a knowledge base that predicts in vivo efficacy, allowing for optimized combination dosing that achieves superior antimicrobial activity while managing toxicity.
3Object-affected harmful factors
If novel antimicrobial agents with new modes of action are developed, then resistance is reduced, but development complexity increases
Solution Approach 1:
The invention merges two existing drug classes (backbone-cyclized peptides and small molecule antibiotics) into a single combination therapy that targets multiple resistance mechanisms simultaneously. This merging approach achieves novel modes of action through synergistic interaction while leveraging the development infrastructure of existing components, thereby reducing overall development complexity compared to creating entirely new antimicrobial agents from scratch.
Data Source
AI summary
A novel combination comprising a β-hairpin peptidomimetic of the formula cyclo(-Thr-Trp-Ile-Dab-Orn-DDab-Dab-Trp-Dab-Dab-Ala-Ser-DPro-Pro) (I), and a further compound with antibiotic activity, that enable therapeutic control of specific bacterial infections in human or animals at doses of the individual compounds lower than either of the compounds administered alone. The combination can be used as a medicament to treat e.g. skin or soft tissue infections; eye, ear, blood stream, or intra-abdominal infections; infections related to respiratory diseases, to bone diseases, to cardiovascular diseases, to genitourinal diseases, or to gastrointestinal diseases.