Modified Bacteria for Enhanced Bioproduction via Toxin-Antitoxin Removal
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Solution Overview
Problem
Current bioproduction systems face challenges in achieving commercially viable scales and titers due to the long time scales and high risks associated with engineering productive bacterial strains, as well as limitations in rapidly prototyping and screening pathways, leading to inefficient production of value-added molecules.
Innovation Solution
Modified bacteria with reduced or removed stress response effector proteins, specifically by modifying the expression of type I and/or type II toxin-antitoxin system proteins and structural proteins that modulate ribosomes, to enhance bioproduction of desirable chemicals and products.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional metabolic engineering techniques are used to engineer productive bacterial strains, then pathway flux can be increased through gene deletion, disruption, or overexpression, but the process requires long time scales and carries high risks associated with substantial engineering of native metabolism
Solution Approach 1:
The patent extracts and removes stress response effector proteins (toxin-antitoxin systems and ribosome-modulating proteins) from the bacterial system. By taking out these harmful components that cause metabolic shutdown during stress, the system achieves enhanced bioproduction without requiring extensive iterative strain engineering, thereby reducing both time and risk
Solution Approach 2:
The patent changes the physiological state of the bacteria by modifying the expression levels of stress response genes. By altering the parameters of stress response activity (reducing toxin-antitoxin system activity), the system transitions from a stress-induced metabolic shutdown state to an enhanced production state, achieving higher titers more rapidly
2Reliability
If stress response effector proteins are present in bacteria during bioproduction, then cellular stress response mechanisms are activated, but this leads to metabolic shutdown and reduced bioproduction of value-added molecules
Solution Approach 1:
The patent converts the harmful effect of stress response activation into a benefit by selectively removing only the effector proteins (toxins) while preserving the sensing mechanisms. This allows the cell to sense stress without executing the harmful metabolic shutdown response, thereby maintaining reliability of stress sensing while eliminating the harmful impact on productivity
Solution Approach 2:
The patent extracts and removes specific stress response effector proteins (toxin-antitoxin systems and ribosome-modulating proteins) from the bacterial system. By taking out these harmful components that cause metabolic shutdown, the system achieves enhanced bioproduction while maintaining cellular reliability through preserved sensing capabilities
3Productivity
If numerous genetic changes are implemented to improve pathway flux, then production efficiency can be enhanced, but the complexity of strain engineering increases and creates bottlenecks in the improvement pipeline
Solution Approach 1:
The patent achieves enhanced pathway flux through a simplified approach: modifying the expression parameters of a limited set of stress response genes rather than implementing numerous genetic changes across the pathway. This parameter change strategy reduces engineering complexity while maintaining productivity improvements
Solution Approach 2:
The patent applies a universal solution that works across different pathways and production systems by removing general stress response effectors rather than pathway-specific optimizations. This multi-functional approach simplifies the engineering process while enhancing productivity across diverse bioproduction applications
Data Source
AI summary
The present disclosure relates generally to modified bacteria, such as E. coli, with modification in the expression of at least one gene encoding a type I and/or type II toxin-antitoxin (TA) system protein and/or at least one gene encoding a structural protein that modulates ribosomes and methods of using the disclosed bacteria for producing a biological compound of interest. The modifications of the bacteria result in enhanced bioproduction.