Engineered Bacterium T6SS Delivery Platform for Antibacterial Treatments
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Solution Overview
Problem
The emergence of antibiotic-resistant pathogens, particularly gram-negative bacteria, poses a significant threat due to the overuse and misuse of antibiotics in human therapy, agriculture, and aquaculture, leading to infections in humans and significant losses in aquaculture and agriculture, necessitating an alternative antibacterial platform.
Innovation Solution
A genetically engineered non-pathogenic bacterium is developed with a gene cluster encoding an antibacterial protein delivery platform linked to an inducible positive regulation system, utilizing an engineered Type VI secretion system (T6SS) that can be activated by external signals, allowing for controlled delivery of antibacterial effectors and immunity pairs, thereby exerting antibacterial activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotics are used extensively for human therapy and agriculture, then public health benefits are improved, but antibiotic-resistant pathogens emerge and become resistant to multiple drugs
Solution Approach 1:
The patent uses the T6SS system, originally evolved for bacterial competition and pathogenicity, and converts it into a beneficial antibacterial tool against multidrug-resistant pathogens. The effector proteins that naturally kill competing bacteria are harnessed to target antibiotic-resistant pathogens, transforming a potentially harmful mechanism into a therapeutic benefit
Solution Approach 2:
The patent introduces a non-pathogenic bacterium as an intermediary carrier that delivers antibacterial effectors to pathogenic bacteria. This non-pathogenic host serves as a safe vehicle to deliver the T6SS machinery without causing disease, mediating between the effector proteins and the target pathogens
2Reliability
If a protein delivery platform is activated continuously, then antibacterial activity is maintained, but energy is wasted and unintended activation may occur
Solution Approach 1:
The patent implements dynamic regulation of the T6SS gene cluster through inducible promoters that respond to environmental signals. The system transitions from an inactive state to an active state only when specific inducing conditions are met, allowing the bacterium to adapt its antibacterial activity to environmental demands rather than maintaining constant activity
Solution Approach 2:
The inducible expression system creates periodic activation of the T6SS platform, where the system remains dormant until triggered by specific environmental cues and then activates temporarily to deliver antibacterial effectors. This periodic action conserves energy compared to continuous activation
3Loss of time
If the T6SS gene cluster includes all native regulators, then the system is self-regulating, but it cannot be externally controlled for inducible expression
Solution Approach 1:
The patent extracts the native positive regulators (VP1407 and VP1391) from the T6SS gene cluster and replaces them with externally controllable inducible expression systems. This extraction of the self-regulation mechanism allows independent control of effector expression and delivery platform activation through external inducing agents
Solution Approach 2:
The patent creates a universal platform where the T6SS delivery machinery can be controlled through multiple different inducing mechanisms. The system can respond to various environmental signals and can be tailored to different induction methods, making it versatile for different application scenarios
4Adaptability or versatility
If the bacterium is engineered to deliver multiple effector proteins, then target range is expanded, but the risk of transformation into pathogenic form increases
Solution Approach 1:
The patent confers antibacterial properties locally to the non-pathogenic bacterium through targeted genetic engineering of specific T6SS components and effector proteins. The engineered bacterium acquires localized antibacterial functionality without gaining systemic pathogenic capabilities, maintaining its non-pathogenic nature while delivering therapeutic effectors
Solution Approach 2:
The non-pathogenic bacterium serves as a safe intermediary that delivers antibacterial effectors to pathogens without becoming pathogenic itself. The host bacterium acts as a controlled platform that can carry multiple effector genes but lacks the virulence factors needed to cause disease, separating the delivery function from pathogenicity
Data Source
AI summary
Provided herein is a non-pathogenic bacterium comprising a gene cassette encoding an antibacterial protein delivery platform, wherein the gene cassette is operably linked to a positive regulator inducibly-expressed from a genomic location.