Amyloid Peptides Induce Beta-Lactamase Aggregation
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Solution Overview
Problem
Current strategies for combating bacterial antibiotic resistance, particularly against beta-lactam antibiotics, face challenges due to the rapid evolution of beta-lactamases, with existing inhibitors exerting selective pressure and potentially accelerating enzyme evolution, and the need for novel approaches to target resistance mechanisms.
Innovation Solution
Development of synthetic amyloid-forming peptides that specifically target aggregation-prone regions of beta-lactamases, such as TEM and SHV, to induce protein misfolding and inactivation, thereby restoring sensitivity to beta-lactam antibiotics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mechanism-based inhibitors (substrate analogs) are used to target beta-lactamase active sites, then enzyme activity is inhibited, but selective pressure accelerates beta-lactamase evolution and resistance
Solution Approach 1:
Instead of targeting the active site of beta-lactamases (conventional approach), the invention targets aggregation-prone regions (APRs) outside the active site to induce protein aggregation and inactivation. This inverted approach avoids direct competition at the active site, thereby reducing selective pressure while achieving enzyme inactivation through a fundamentally different mechanism.
Solution Approach 2:
The invention uses small molecules as intermediaries that bind to aggregation-prone regions and mediate protein aggregation. These molecules do not directly inhibit the enzyme's catalytic function but rather act as mediators that induce misfolding and aggregation, providing an indirect mechanism of enzyme inactivation that bypasses the selective pressure problem.
2Reliability
If traditional small molecule inhibitors are used, then beta-lactamase activity is inhibited, but the development speed is limited compared to peptide-based approaches
Solution Approach 1:
The invention changes the fundamental parameter of inhibition mechanism from active site competition to aggregation induction. This parameter change enables the use of peptide-based molecules with different structural and functional properties, allowing for faster development and adaptation to new beta-lactamase variants through sequence modification rather than de novo small molecule design.
3Adaptability or versatility
If broad-spectrum inhibitors are designed to target multiple beta-lactamase variants, then coverage is improved, but specificity and effectiveness against individual variants decrease
Solution Approach 1:
The invention applies universality by designing peptides that target conserved aggregation-prone regions common across different beta-lactamase classes (A, B, C, D). These peptides achieve multi-functionality by inducing aggregation in various enzyme types while maintaining the ability to optimize for specific variants through sequence adjustments, thus balancing broad coverage with variant-specific effectiveness.
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 peptides selectively aggregate beta-lactamases, rendering bacteria susceptible to beta-lactam antibiotics without being lethal, offering a faster and more targeted approach to addressing emerging enzyme variants compared to traditional small molecule inhibitors.
Implementation Method 1
They are able to form an intermolecular beta-sheet with a bacterial ESBL protein, in particular an ESBL protein of class A
Implementation Method 2
The peptides selectively aggregate beta-lactamases, rendering bacteria susceptible to beta-lactam antibiotics
Data Source
AI summary
The present invention relates to the field of microbiology, in particular to the field of bacterial antibiotic resistance. more particularly to the field of resistance to beta-lactam inhibitors. The invention provides non-natural compounds which induce the aggregation of beta-lactamases, particularly beta-lactamases of class A. In addition, the invention provides combination therapies and pharmaceutical compositions between the non-natural molecules and beta-lactam antibiotics.