Peptide Macrocycles for Resistant Acinetobacter baumannii Infections
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Solution Overview
Problem
Acinetobacter baumannii has developed significant antibiotic resistance, making it difficult to treat infections caused by this bacterium, particularly in intensive care units, with limited treatment options and high mortality rates due to its ability to upregulate resistance determinants and persist in nosocomial settings.
Innovation Solution
Development of novel peptide macrocycles that exhibit activity against both drug-susceptible and drug-resistant strains of Acinetobacter baumannii, with compounds tested against standard strains and clinical isolates showing potential for further development based on pharmacokinetic profiles and efficacy in mouse septicemia models.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibiotics are used to treat Acinetobacter baumannii infections, then treatment options are limited, but antibiotic resistance develops making treatment ineffective
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of peptide compounds to create macrocyclic structures with specific properties. The compounds feature variable substituents (R1-R6) that can be adjusted to optimize activity against resistant strains while maintaining stability. This structural parameter modification allows the peptides to overcome resistance mechanisms that have rendered conventional antibiotics ineffective.
Solution Approach 2:
The invention uses composite materials by creating peptide macrocycles that combine multiple amino acid residues with cyclic structures. These composite molecular structures integrate hydrophobic and hydrophilic regions, allowing simultaneous interaction with multiple targets on the bacterial surface, thereby overcoming single-target resistance mechanisms of conventional antibiotics.
2Adaptability or versatility
If new peptide macrocycles are developed to overcome resistance, then treatment options improve, but development complexity and time increase
Solution Approach 1:
The patent applies segmentation by dividing the peptide macrocycle into distinct functional modules with variables R1 through R6. Each substituent position can be independently optimized for specific properties such as membrane permeability, binding affinity, or stability. This modular approach allows systematic development of analogs with improved activity against resistant strains without completely redesigning the core structure.
Solution Approach 2:
The invention achieves universality by designing a core macrocyclic structure that can accommodate multiple different substituents (R1-R6), allowing a single scaffold to provide activity against various resistant strains. The standardized core structure with variable positions enables broad-spectrum activity while simplifying the development process through structure-activity relationship studies.
3Adaptability or versatility
If peptide macrocycles are designed for broad-spectrum activity, then treatment versatility improves, but selective toxicity against bacteria may decrease
Solution Approach 1:
The patent applies local quality by designing specific regions of the peptide macrocycle with distinct functions. The cyclic core provides structural stability and membrane interaction, while specific substituent positions (R1-R6) are optimized for binding to bacterial targets. This localized functional assignment allows broad-spectrum activity through target interaction while maintaining selective toxicity by concentrating antimicrobial activity at specific molecular sites rather than through non-specific mechanisms.
Data Source
AI summary
The present invention provides compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8,R 8', R9, R9', X1, X2, X3, X4, X5, X6, X7, X8, X9 and X10 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by Acinetobacter baumannii.