AIP Mimetics for Staphylococcus Quorum Sensing Inhibition

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Solution Overview

Problem

Current peptidic AgrC modulators for Staphylococcus aureus are limited by hydrolytic instability, proteolytic susceptibility, low water solubility, and challenges in large-scale synthesis, necessitating the development of non-peptide, small molecule mimetics with enhanced stability and solubility.

Innovation Solution

Development of structurally simplified autoinducing peptide (AIP) mimetics that modulate AgrC activity in Staphylococcus aureus, including compounds that inhibit or activate AgrC receptors, offering pan-group inhibition and improved synthetic feasibility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If peptidic AgrC modulators are used to inhibit quorum sensing in Staphylococcus aureus, then quorum sensing inhibition activity is achieved, but hydrolytic instability and proteolytic susceptibility occur

Engineering Contradiction:

Improvequorum sensing inhibition activityVSAvoidhydrolytic stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent creates simplified mimetics that copy the essential functional features of AIPs without replicating their full peptidic structure. These mimetics retain the ability to bind AgrC and inhibit quorum sensing while using non-peptide chemical scaffolds that resist hydrolysis and proteolysis, thus achieving reliability without the stability problems of the original peptides

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The invention fundamentally changes the chemical parameters of the modulators by transitioning from peptidic to non-peptide structures. This parameter change includes altering the chemical composition, bonding types, and molecular architecture to create compounds with enhanced stability while maintaining biological activity

Inventive Principle:

Principle #35Parameter changes

2Reliability

If peptidic AgrC modulators are used to inhibit quorum sensing in Staphylococcus aureus, then quorum sensing inhibition activity is achieved, but low water solubility occurs

Engineering Contradiction:

Improvequorum sensing inhibition activityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the physicochemical parameters of the modulators by replacing peptidic structures with non-peptide analogs that have improved aqueous solubility. The simplified mimetics incorporate structural features that enhance water solubility while preserving the key interactions needed for AgrC binding and quorum sensing inhibition

Inventive Principle:

Principle #35Parameter changes

3Reliability

If peptidic AgrC modulators are used to inhibit quorum sensing in Staphylococcus aureus, then quorum sensing inhibition activity is achieved, but challenges in large-scale synthesis occur

Engineering Contradiction:

Improvequorum sensing inhibition activityVSAvoidsynthetic feasibility

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent creates simplified copies of AIPs that can be manufactured more easily. The non-peptide mimetics use chemical structures and synthetic routes that are more amenable to large-scale production compared to the complex peptidic structures, reducing manufacturing challenges while maintaining biological activity

Inventive Principle:

Principle #26Copying

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 AIP mimetics effectively block hemolysis, reduce Toxic shock syndrome toxin-1 production, and modulate biofilm formation in Staphylococcus aureus, providing potent and stable alternatives for treating infections and interfering with quorum sensing.

Implementation Method 1

Quorum sensing (QS) allows bacteria to behave as a group at high cell densities and is closely connected to virulence in many common pathogens. This intercellular communication system is mediated by small molecule or peptide signals that diffuse out of or are secreted by bacteria into the local environment.

Methodology Applied

Scientific EffectQuorum sensing:

Implementation Method 2

Many of these efforts have focused on the development of synthetic mimics of QS signals that can inhibit QS receptor:signal binding, for use as chemical probes to block virulence phenotypes, and to delineate basic QS mechanisms.

Methodology Applied

Scientific EffectCompetitive inhibition:

Data Source

PatentUS12139464B2Simplified structural mimetics of AIPS as quorum sensing inhibitors

Publication Date: 2024.11.12 THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE NAVY

AI summary

Compounds provided are racemic, non-racemic or substantially enantiomerically pure dimers or salts or solvates thereof of formula:where:W and W′ are S or NR1, or —W—CO— or —W—CO— is —CH═CH—, where each R1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R and R′ are hydrogen or an straight-chain or branched alkyl group having 1-3 carbon atoms; R3 and R′3 are hydrogen or a C1-C3 alkyl; X1, X′1, X2 and X′2 are optionally-substituted straight-chain or branched alkyl groups having 3-8 carbon atoms, optionally-substituted cycloalkyl groups having 3-12 carbon atoms; optionally-substituted aryl, optionally-substituted heteroaryl, optionally-substituted heterocycyl, optionally-substituted cycloalkylalkyl, optionally-substituted arylalkyl, optionally-substituted heteroarylalkyl and optionally-substituted heterocycylalkyl groups and L1, L′1 and L2 are divalent chemical moieties. Dimers are employed to modulate quorum sensing and to thus inhibit virulence in Staphylococcus bacteria. Dimers are useful in treating infections of Staphylococcus bacteria. Methods for treating such bacterial infections are also provided.