ORF141-Mutant Staphylococcus Phages for Restoring β-Lactam Susceptibility

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Solution Overview

Problem

The rise of antibiotic-resistant bacterial strains, particularly methicillin-resistant Staphylococcus aureus (MRSA), poses a significant threat to human health due to their difficulty in treatment and high mortality rates.

Innovation Solution

Development of Staphylococcus bacteriophages with knockout and/or nonsense mutations in open reading frame 141 (ORF141) to increase infectivity and susceptibility of MRSA to β-lactam antibiotics, reducing bacterial virulence and oxidative stress.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If bacteriophage with knockout mutation in ORF141 is used to treat MRSA, then susceptibility to β-lactam antibiotics is enhanced, but bacterial resistance to phage infection develops

Engineering Contradiction:

Improvesusceptibility to β-lactam antibioticsVSAvoidresistance to phage infection

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The bacteriophage is engineered with a pre-designed knockout mutation in ORF141 before administration. This preliminary genetic modification enables the phage to specifically target and infect MRSA bacteria, inducing loss of β-lactam resistance through activation of alternative resistance mechanisms that can be subsequently reversed or exploited by antibiotic treatment

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention changes the genetic parameter of the bacteriophage by introducing a knockout mutation in ORF141. This parameter change alters the phage's infectivity profile and its ability to modulate bacterial gene expression, specifically triggering loss of β-lactam resistance in MRSA through regulatory pathway activation

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If bacteriophage treatment is applied to MRSA, then virulence is reduced, but treatment complexity increases

Engineering Contradiction:

Improvebacterial virulenceVSAvoidtreatment complexity

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The bacteriophage treatment extracts or removes the virulence factors from MRSA bacteria through infection-induced gene expression changes. The phage triggers downregulation of virulence genes and loss of resistance markers, effectively separating the harmful virulence properties from the bacterial population without requiring direct removal of the bacteria themselves

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The bacteriophage acts as an intermediary agent between the treatment protocol and the MRSA bacteria. Rather than directly applying antibiotics or anti-virulence agents, the phage mediates the effect by infecting bacteria and triggering internal regulatory changes that reduce virulence and resistance, simplifying the overall treatment approach

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20260014217A1Compositions and methods for bacteriophage infection of staphylococcus bacteria

Publication Date: 2026.01.15 WISCONSIN ALUMNI RES FOUND

AI summary

This disclosure provides Staphylococcus bacteriophages comprising a knockout and/or nonsense mutation in open reading frame 141 (ORF141), or a homologous position thereof. Also provided are compositions comprising the bacteriophage, methods of treating a bacterial infection, and methods of making a bacteria more susceptible to β-lactam antibiotic drug treatment.