Engineered Phage Genome Conversion to Lytic Pathway
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Solution Overview
Problem
Antibiotic resistance in pathogenic bacteria poses a challenge for effective infection control, as broad-spectrum antibiotics can contribute to resistance development, necessitating alternative methodologies for targeted bacterial treatment.
Innovation Solution
The development of engineered viruses, specifically phages, that target pathogenic bacteria by identifying and modifying prophage sequences to convert temperate phages into lytic phages, allowing for precise infection and killing of target organisms without integrating into the bacterial genome, thereby avoiding resistance development.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If broad-spectrum antibiotics are used to treat bacterial infections, then infection control is achieved, but antibiotic resistance develops in pathogenic bacteria
Solution Approach 1:
The patent extracts and utilizes naturally occurring bacteriophages that specifically target pathogenic bacteria. By isolating phages from environmental samples and engineering them for enhanced activity, the invention provides an alternative therapeutic agent that does not contribute to antibiotic resistance, thus resolving the contradiction between effective infection control and resistance development
Solution Approach 2:
The patent modifies phage parameters through genetic engineering to optimize their therapeutic properties. This includes altering phage host-range genes to expand or narrow specificity, modifying lysis genes to control killing kinetics, and engineering phage stability parameters. These parameter changes enable tailored treatments that maintain efficacy while avoiding resistance
2Reliability
If temperate phages are used to target bacteria, then bacterial infection is treated, but the phage integrates into the bacterial genome rather than killing the target
Solution Approach 1:
The patent removes the integrase gene from temperate phage genomes through genetic engineering. By deleting this specific gene responsible for genome integration, the modified phages lose their ability to form prophages and instead exclusively follow the lytic pathway, ensuring target bacterial cell death rather than silent integration
Solution Approach 2:
The patent inverts the natural lifecycle choice of temperate phages by engineering them to exclusively pursue the lytic pathway. Through deletion of integrase and modification of regulatory elements, the phage is forced to abandon the lysogenic option and commit to killing the host cell, thus converting a potentially harmful integration event into a therapeutic lytic event
3Productivity
If lytic phages are engineered to kill target bacteria, then bacterial infection is effectively treated, but the phage may integrate into the genome and reduce killing efficiency
Solution Approach 1:
The patent removes the integrase gene and other lysogeny-related genes from the phage genome. This extraction of integration capability ensures that the phage cannot switch to a lysogenic state, maintaining consistent lytic behavior and reliable bacterial killing efficiency across multiple infection cycles
Solution Approach 2:
The patent engineers regulatory feedback mechanisms into the phage genome that monitor host cell conditions and reinforce the lytic pathway. When the phage detects suitable host conditions, feedback loops activate lytic gene expression and suppress any residual integrase activity, ensuring consistent lytic commitment and predictable killing efficiency
Data Source
AI summary
The present invention relates, in part, to engineered viruses (e.g., engineered phages), phage cocktails, and methods of producing and/or identifying viruses for targeting pathogenic bacteria.