Engineered Lactobacillus Delivery of Gut Anti-Infective Biomolecules
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Solution Overview
Problem
Existing direct fed microbials (DFMs) fail to produce anti-infective factors in sufficient quantities to effectively target a broad range of pathogens, leading to vulnerability of hosts to multiple pathogens, and traditional antibiotics face issues with duration, delivery, and antibiotic resistance.
Innovation Solution
A genetically modified microorganism, such as Lactobacillus reuteri, engineered with an expression cassette containing promoters, signal sequences, cell-wall anchors, and heterologous coding regions for biomolecules like bactericidal peptides and antibodies, to continuously deliver anti-infective factors to the gastrointestinal or respiratory tract.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional antibiotics are administered to the host animal, then anti-infective activity is achieved, but the duration of action is limited and repeated administration is required
Solution Approach 1:
The genetically modified microorganism serves itself by continuously producing and secreting anti-infective molecules within the host's gastrointestinal tract, eliminating the need for external re-administration. The microorganism acts as a self-sustaining delivery system that maintains therapeutic levels of anti-infective activity over extended periods through its own metabolic processes and replication.
Solution Approach 2:
The microorganism is pre-engineered with multiple heterologous genes encoding different anti-infective molecules, signal sequences for secretion, and promoter elements before administration. This preliminary genetic preparation enables the microorganism to immediately begin producing and secreting anti-infective factors upon colonization, providing continuous protection without waiting for external intervention.
2Adaptability or versatility
If stronger or more broad-spectrum antibiotics are administered, then the scope of pathogen coverage is improved, but antibiotic resistance development increases
Solution Approach 1:
The invention changes the fundamental parameter of anti-infective delivery from exogenous antibiotic administration to endogenous production by genetically modified microorganisms. By altering the source and mode of delivery, the system achieves broad-spectrum pathogen coverage through multiple different anti-infective molecules produced simultaneously, while avoiding the selection pressure that drives antibiotic resistance development.
Solution Approach 2:
The genetically modified microorganism functions as a composite biological system containing multiple heterologous genes encoding different types of anti-infective molecules (e.g., bacteriocins, antibiotics, enzymes). This composite genetic architecture enables the microorganism to produce a diverse arsenal of anti-infective factors with different mechanisms of action, providing broad-spectrum coverage while reducing resistance risk through multi-target attack.
3Ease of operation
If oral delivery of antibiotics is used, then ease of administration is improved, but degradation of the antibiotic and failure to deliver to the target site occur
Solution Approach 1:
The genetically modified microorganism acts as a living intermediary carrier that protects anti-infective molecules from degradation during oral administration. The microorganism's cellular structure and secretory apparatus serve as a protective vehicle, delivering functional anti-infective factors directly to the gastrointestinal tract target site while bypassing the degradation issues that affect free antibiotics administered orally.
Solution Approach 2:
The microorganism uses its own natural secretory pathways and cellular machinery to produce, process, and deliver anti-infective molecules to the target site. This self-service capability ensures proper folding, modification, and secretion of the anti-infective factors, guaranteeing their stability and functionality upon reaching the gastrointestinal tract without requiring external protection or delivery systems.
4Device complexity
If direct fed microbials produce anti-infective factors, then the delivery system is simplified, but the quantity produced is insufficient to effectively target pathogens
Solution Approach 1:
The genetically modified microorganism serves multiple functions simultaneously: it acts as a probiotic colonizer, a factory for producing anti-infective molecules, a secretion system for delivering those molecules, and a self-replicating population that maintains continuous production. This multi-functionality allows a single organism to achieve both system simplicity and high-level anti-infective factor production.
Solution Approach 2:
The invention changes the production capacity parameter by introducing multiple heterologous genes with strong promoter elements into the microorganism's genome. This genetic enhancement transforms the microorganism from a low-level producer to a high-capacity factory, enabling it to synthesize and secrete sufficient quantities of anti-infective factors to effectively target and control pathogen populations in the host.
Data Source
AI summary
The present invention relates to efficient delivery of anti-infective activity, immunomodulatory factors, or growth-promoting biomolecules directly to the digestive tract of an animal via a live delivery platform. The live delivery platform can be a genetically modified microorganism. Delivery can be accomplished with a Lactobacillus sp which colonizes the gastrointestinal tract. The anti-infective activity can be a bacteriocidal or bacteriostatic peptide, an antibody or fragment thereof which specifically recognizes a pathogen, or a phage, or a lytic peptide from a phage which specifically targets a certain pathogen.