Retron-Based Phage Genome Engineering for Host Range and Defense Evasion
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Solution Overview
Problem
Antibiotic resistance in bacteria is increasing globally, making it difficult to treat common infections, and existing bacteriophages are limited in their host range and susceptible to bacterial anti-phage defenses.
Innovation Solution
Genetically modify bacteriophages using reverse-transcribed editing templates and bacterial host cells to introduce targeted genomic edits, enabling them to evade bacterial defenses and target specific pathogens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If natural bacteriophages are used to target bacteria, then they can kill bacteria, but they are limited in host range and susceptible to bacterial anti-phage defenses
Solution Approach 1:
The patent applies preliminary action by pre-modifying bacteriophage genomes in bacterial host cells using retron-based editing systems before deployment. Multiple genomic edits are introduced simultaneously to equip phages with enhanced host range and resistance to anti-phage defenses in advance, rather than attempting modifications after the phages encounter resistant bacteria
Solution Approach 2:
The patent employs parameter changes by systematically modifying multiple parameters of the bacteriophage genome simultaneously using retron editing templates. These modifications include altering receptor binding proteins to expand host range, and introducing mutations to evade CRISPR-Cas systems and other bacterial defenses, thereby transforming the phage's biological properties
2Adaptability or versatility
If multiple modifications are introduced into phage genomes simultaneously, then engineered bacteriophages can target bacteria more effectively, but the complexity of the editing process increases
Solution Approach 1:
The patent applies merging by combining multiple editing functions into a single retron-based editing system operating within bacterial host cells. The system integrates template RNA synthesis, reverse transcription to DNA, and recombination into the phage genome, enabling simultaneous introduction of multiple genomic modifications through one unified process rather than separate editing steps
Solution Approach 2:
The patent employs self-service by utilizing the bacterial host cell's own molecular machinery to perform the editing functions. The host cell provides reverse transcriptase activity, recombination enzymes, and other necessary components, eliminating the need for complex external editing apparatus and simplifying the overall process
3Adaptability or versatility
If phage propagation through multiple host cell populations is performed, then multiple engineered modifications can be introduced, but the time and resources required increase
Solution Approach 1:
The patent merges multiple editing functions into a single retron-based system that operates within one host cell population. This allows simultaneous introduction of multiple genomic modifications in a single propagation cycle, eliminating the need for sequential editing across multiple host populations and significantly reducing time requirements
Solution Approach 2:
The retron editing system exhibits multi-functionality by capable of introducing various types of genomic modifications (point mutations, insertions, deletions) at multiple locations within the phage genome simultaneously. This universal editing capability replaces the need for specialized editing procedures for each modification type
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 modified bacteriophages can effectively target and eliminate antibiotic-resistant bacteria, offering a therapeutic and industrial solution by enhancing their host range and evasion of anti-phage defenses.
Implementation Method 1
a reverse-transcribed editing template, which edits the phage genome during replication
Data Source
AI summary
Systems and methods for editing bacteriophages are described herein.