Peptide Macrocycles Against Acinetobacter baumannii Resistance

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Solution Overview

Problem

Acinetobacter baumannii has developed significant antibiotic resistance, making existing treatments ineffective, particularly for Multi-Drug Resistant (MDR) and Carbapenem-resistant strains, which are difficult to treat and pose a high risk in healthcare settings with high mortality and morbidity rates.

Innovation Solution

Development of novel compounds of formula (I), which include specific structural elements such as carboxylic acid bioisosteres and amino groups, synthesized through reductive amination and cyclization processes, to create potent antimicrobial agents effective against Acinetobacter baumannii.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing antimicrobial agents are used against Acinetobacter baumannii, then treatment options are limited, but the bacteria have developed significant resistance making these agents ineffective

Engineering Contradiction:

Improveeffectiveness of antimicrobial treatmentVSAvoidantibiotic resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of peptide macrocycles by changing parameters such as incorporating non-natural amino acids, adjusting side chain lengths (R1-R10), and modifying the macrocyclic ring structure. These parameter changes enable the compounds to overcome antibiotic resistance while maintaining antimicrobial activity against Acinetobacter baumannii

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite peptide macrocycle structures combining natural amino acid residues with non-natural amino acid modifications. This composite approach allows the molecules to exhibit enhanced antimicrobial activity and resistance to bacterial efflux pumps and degradation enzymes

Inventive Principle:

Principle #40Composite materials

2Ease of manufacture

If Multi-Drug Resistant A. baumannii infections are treated with available therapeutic options, then treatment difficulty increases, but mortality and morbidity rates remain high

Engineering Contradiction:

Improvetreatability of MDR infectionsVSAvoidmortality and morbidity rates

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent divides the peptide macrocycle into modular segments with specific functional regions: the macrocyclic core structure, side chain substituents (R1-R10), and terminal groups. This segmentation allows independent optimization of each region for activity against specific resistance mechanisms while maintaining overall therapeutic efficacy

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention synthesizes novel peptide macrocycles that copy and expand upon the structural framework of natural peptide antibiotics, incorporating non-natural amino acids and modified side chains to overcome MDR barriers while maintaining biological activity

Inventive Principle:

Principle #26Copying

3Adaptability or versatility

If carbapenem-resistant A. baumannii is treated with conventional antimicrobials, then treatment options become limited, but the complexity of resistance mechanisms increases

Engineering Contradiction:

Improvetreatment option availabilityVSAvoidresistance mechanism complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent introduces dynamic structural features in the peptide macrocycles, including flexible side chains and configurable macrocyclic rings that can adapt their conformation to interact with various resistance mechanisms. This dynamic capability allows the compounds to effectively target carbapenem-resistant strains despite the complexity of their resistance profiles

Inventive Principle:

Principle #15Dynamics

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 compounds demonstrate strong activity against Acinetobacter baumannii, offering a potential solution for treating infections caused by this resistant bacterium, including bacteremia, pneumonia, meningitis, and urinary tract infections, with the aim of reducing mortality and morbidity rates.

Implementation Method 1

synthesized through reductive amination and cyclization processes

Methodology Applied

Scientific EffectReductive amination: Redox Reactions

Data Source

PatentUS11505573B2Peptide macrocycles against <i>Acinetobacter baumannii</i>

Publication Date: 2022.11.22 F HOFFMANN LA ROCHE INC

AI summary

The present invention provides compounds of formula (I)wherein X, L1 and R1 to R10 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.