BPEI-antibiotic combination resensitizes MRSA via electrostatic binding

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Solution Overview

Problem

Methicillin-resistant Staphylococcus aureus (MRSA) strains have developed resistance to conventional antibiotics, rendering existing treatments ineffective, and there is a need for new formulations that can resensitize these bacteria to historical antibiotics like ampicillin and methicillin.

Innovation Solution

The use of branched poly(ethylenimine) (BPEI), a cationic polyamine, in combination with antibiotics such as ampicillin and methicillin, which synergistically reduces the minimum inhibitory concentration (MIC) of these antibiotics against MRSA, effectively resensitizing the bacteria and enhancing their antimicrobial efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antibiotics are used to treat MRSA infections, then treatment is effective against susceptible bacteria, but the antibiotics become ineffective due to bacterial resistance

Engineering Contradiction:

Improveantibiotic effectivenessVSAvoidbacterial resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces BPEI as an intermediary substance that mediates between the antibiotic and the resistant bacteria. BPEI binds to the bacterial cell wall components (teichoic acids and peptidoglycan), creating a complex that allows the antibiotic to interact with its target PBP2a enzyme despite the presence of resistance mechanisms. This intermediary approach restores antibiotic effectiveness without requiring new antibiotic development.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates a composite therapeutic system consisting of BPEI in combination with conventional antibiotics. This composite approach leverages the cell-wall-binding properties of BPEI and the enzyme-inhibiting properties of β-lactam antibiotics to overcome resistance. The composite material strategy allows repurposing of existing antibiotics against resistant strains through combination with BPEI.

Inventive Principle:

Principle #40Composite materials

2Reliability

If drugs of last resort (vancomycin, linezolid, daptomycin) are administered to treat MRSA, then bacterial growth is inhibited, but treatment is delayed until after toxin-mediated tissue injury has occurred

Engineering Contradiction:

Improveantibacterial activityVSAvoidtreatment delay

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent enables preliminary action by restoring the effectiveness of conventional antibiotics that can be administered earlier in the disease course. By using BPEI in combination with antibiotics like ampicillin or methicillin, clinicians can initiate treatment before toxin-mediated damage becomes irreversible, rather than waiting for MRSA diagnosis and then administering last-resort drugs. This preliminary restoration of antibiotic efficacy prevents the time loss associated with delayed treatment.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If vancomycin is used as a primary treatment option for MRSA, then antibiotic efficacy is maintained, but treatment cost and toxicity increase

Engineering Contradiction:

Improveantibiotic efficacyVSAvoidtoxicity and cost

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the therapeutic parameters by combining conventional antibiotics with BPEI, which alters the minimum inhibitory concentration (MIC) dynamics against MRSA. This parameter change allows the use of cheaper, less toxic antibiotics at modified dosing regimens that achieve efficacy comparable to vancomycin. The BPEI-antibiotic complex achieves bacterial inhibition at concentrations that reduce toxicity while maintaining reliability.

Inventive Principle:

Principle #35Parameter changes

4Reliability

If β-lactamase inhibitors or efflux-pump inhibitors are used to overcome resistance, then antibiotic susceptibility is restored, but side effects and slow translation to clinical usage occur

Engineering Contradiction:

Improveantibiotic susceptibilityVSAvoidclinical implementation

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent employs conventional β-lactam antibiotics in combination with BPEI as a disposable, easily implementable solution that does not require complex dosing regimens or monitoring. Unlike β-lactamase inhibitors that require precise timing and dosing, the BPEI-antibiotic combination can be administered as a straightforward formulation, facilitating rapid clinical implementation. The approach uses readily available antibiotics rather than requiring development and approval of new inhibitor compounds.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 BPEI-antibiotic combination significantly reduces the MIC of antibiotics against MRSA, making them effective again, while demonstrating low toxicity to mammalian cells and preventing the growth of resistant bacteria strains.

Implementation Method 1

branched poly(ethylenimine) (BPEI), a cationic polyamine

Methodology Applied

Scientific EffectElectrostatic interaction: Electrostatics

Implementation Method 2

synergistically reduces the minimum inhibitory concentration (MIC) of these antibiotics against MRSA

Methodology Applied

Scientific EffectSynergistic effect:

Data Source

PatentUS10953040B2Methods of treating bacterial infections with penam β-lactam antibiotics and branched poly(ethylenimine)

Publication Date: 2021.03.23 THE BOARD OF RGT UNIV OF OKLAHOMA

AI summary

The present disclosure describes compositions comprising β-lactam antibiotics and branched polyethylenimines (BPEI), having efficacy against various Gram-positive bacteria, for example Gram-positive bacteria having resistance against β-lactam antibiotics, one non-limiting example of which is Methicillin-resistant Staphylococcus aureus (MRSA). The compositions result in the resensitization of such resistant bacterial strains to traditional antibiotic therapies such as β-lactam antibiotics.