Lytic Bacteriophage Binding Efflux Pumps to Restore Antibiotic Sensitivity

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Solution Overview

Problem

Current methods for managing antibiotic-resistant bacterial infections, particularly those caused by Pseudomonas aeruginosa, are inadequate due to the bacterium's intrinsic resistance and ability to form biofilms, leading to high morbidity and mortality rates in prosthetic vascular graft infections and other conditions.

Innovation Solution

The use of specific lytic bacteriophages such as OMKO1, LPS-5, TIVP-H6, LPS-TLTL, TIVP-27, SFA1-1, SF60B, SFNHSI, SF37B, and U136B that bind to efflux pumps and other surface molecules on bacteria, increasing antibiotic sensitivity and disrupting biofilm formation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If chemical antibiotics are used to treat bacterial infections, then bacterial growth is inhibited, but bacterial resistance to antibiotics increases

Engineering Contradiction:

Improveeffectiveness of antibiotic treatmentVSAvoidantibiotic resistance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent combines bacteriophage therapy with antibiotic treatment to create a synergistic effect. The bacteriophage specifically infects and kills antibiotic-resistant bacteria, while antibiotics continue to suppress susceptible bacteria, together overcoming the problem of antibiotic resistance without sacrificing the effectiveness of either treatment modality

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The bacteriophage acts as an intermediary agent that bridges the gap between antibiotic treatment and antibiotic-resistant bacteria. Instead of directly confronting resistant bacteria with antibiotics (which fails), the phage mediates the killing process by infecting and lysing the resistant bacteria, thereby restoring treatment effectiveness

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If Pseudomonas aeruginosa forms biofilms, then bacterial protection and persistence increase, but susceptibility to antibiotics decreases

Engineering Contradiction:

Improvebacterial persistence in infectionVSAvoidresistance to chemical antimicrobials

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The bacteriophage utilizes the biofilm structure itself as a pathway for infection. Rather than needing to penetrate or disrupt the biofilm matrix, the phage infects bacteria within the biofilm through natural bacterial processes, allowing the treatment to work effectively within the protected environment without requiring additional steps to break down the biofilm structure

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

Instead of trying to remove or disrupt the biofilm to access the bacteria (conventional approach), the patent inverts the strategy by allowing the bacteria to remain in the biofilm and infecting them there. The bacteriophage reverses the conventional treatment logic by targeting bacteria in situ within the biofilm rather than attempting to eliminate the biofilm barrier first

Inventive Principle:

Principle #13The other way round (Inversion)

3Object-affected harmful factors

If efflux pumps are upregulated in bacteria, then antibiotic efflux and resistance increase, but bacteriophage binding and infection efficiency increase

Engineering Contradiction:

Improveantibiotic effluxVSAvoidbacteriophage infection efficiency

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent converts the harmful efflux pump mechanism into a beneficial target for bacteriophage infection. The efflux pumps, which normally expel antibiotics and confer resistance, are expressed on the bacterial surface and serve as attachment points for bacteriophages. This transforms the resistance mechanism into a vulnerability that the phage exploits for efficient infection and killing of the bacteria

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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

This approach effectively increases antibiotic sensitivity and decreases virulence in multi-drug resistant bacteria, including Pseudomonas aeruginosa, by forcing genetic trade-offs that enhance phage resistance while increasing sensitivity to antibiotics, thereby improving treatment outcomes for biofilm-associated infections.

Implementation Method 1

specific lytic bacteriophages such as OMKO1, LPS-5, TIVP-H6, LPS-TLTL, TIVP-27, SFA1-1, SF60B, SFNHSI, SF37B, and U136B that bind to efflux pumps and other surface molecules on bacteria

Methodology Applied

Scientific EffectPhage binding:

Data Source

PatentUS20230074892A1Bacteriophage compositions and uses thereof

Publication Date: 2023.03.09 YALE UNIVERSITY

AI summary

The present invention includes compositions and methods for increasing antibiotic sensitivity and/or decreasing virulence in bacteria.