Antisense Oligomers Targeting Bacterial mRNA
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Solution Overview
Problem
The widespread use of antibiotics has led to antibiotic resistance in many bacterial pathogens, including multi-drug-resistant strains of Escherichia coli and Acinetobacter baumannii, limiting treatment options and raising concerns about a post-antibiotic era.
Innovation Solution
The use of antisense oligomers targeting specific bacterial genes involved in biochemical pathways and antibiotic resistance, such as those associated with RNA biosynthesis, protein biosynthesis, and peptidoglycan biosynthesis, to increase antibiotic susceptibility and reduce bacterial growth, often in combination with classic antibiotics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If classic antibiotics are used to treat bacterial infections, then bacterial infections can be controlled or eliminated, but antibiotic resistance develops in pathogenic bacteria
Solution Approach 1:
The patent introduces antisense oligomers as intermediary molecules that bind to bacterial mRNA and prevent translation, serving as a mediator between the antibiotic and the bacterial target. These oligomers enhance the effectiveness of classic antibiotics by blocking ribosomal function, thereby restoring antibacterial efficacy against resistant strains without directly acting as traditional antibiotics.
Solution Approach 2:
The patent changes the mechanism of action parameter from direct bacterial cell targeting (classic antibiotics) to mRNA translation blocking (antisense oligomers). This parameter change allows the treatment to overcome resistance mechanisms that involve bacterial enzyme production or efflux pumps, as the oligomers act upstream of these resistance mechanisms.
2Reliability
If multiple antibiotics are combined to overcome resistance, then treatment effectiveness increases, but treatment complexity and side effects increase
Solution Approach 1:
The patent merges the mechanism of antisense oligomer action with classic antibiotic therapy in a synergistic combination. The antisense oligomers bind to bacterial mRNA and prevent translation, while classic antibiotics simultaneously target bacterial cell wall synthesis or other processes. This merging of mechanisms at different levels (molecular translation blocking + cellular process inhibition) creates synergistic efficacy against multi-drug resistant bacteria without requiring multiple different antibiotic classes.
3Productivity
If antibiotics are used as feed supplements in poultry and livestock, then growth promotion occurs, but drug resistance in bacteria increases
Solution Approach 1:
The patent extracts the growth promotion function from antibiotic use and replaces it with antisense oligomer therapy. By targeting specific bacterial genes involved in growth pathways, the oligomers can selectively inhibit pathogenic bacteria without the broad-spectrum selective pressure that drives resistance. This extraction allows for growth promotion or infection control without the harmful selection pressure for resistant strains.
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 antisense oligomers demonstrate bactericidal activity at clinically relevant concentrations, enhance antibiotic susceptibility, and show synergy with multiple antibiotics, effectively reducing bacterial growth and minimum inhibitory concentrations of antibiotics against resistant strains.
Implementation Method 1
An antisense oligomer of sufficient length and complementarity to specifically hybridize to an mRNA target sequence
Implementation Method 2
The antisense oligomer is conjugated to a peptide moiety which enhances cellular uptake, either by active or facilitated transport
Data Source
Figure 1A~1E
Figure 1F~1H
Figure 2A
AI summary
Provided are antisense oligomers targeted against or genes associated with a biochemical pathway and/or cellular process, and related compositions and methods of using the oligomers and compositions to treat an infected mammalian subject, for example, as primary antimicrobials or as adjunctive therapies with classic antimicrobials.