Phagemid Decolonization of Antibiotic-Resistant Bacteria
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Solution Overview
Problem
Current methods for decolonizing antibiotic-resistant bacteria from the intestine are inefficient and pose side effects, such as dysbiosis and antibiotic resistance selection, making them unsuitable for clinical use, especially in immunocompromised patients.
Innovation Solution
The use of engineered bacteriophages or packaged phagemids that specifically target and eliminate antibiotic-resistant bacterial strains by modifying their DNA, thereby preventing the recurrence of these strains after treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If selective digestive decontamination with wide spectrum antibiotics is used to eradicate antibiotic resistant bacteria from the intestine, then the carriage of antibiotic resistant bacteria is reduced, but the microbiota is disrupted causing dysbiosis and associated infections
Solution Approach 1:
The invention segments the broad-spectrum antibiotic treatment into targeted, strain-specific phage therapy. Instead of using wide-spectrum antibiotics that affect all bacteria, the patent employs bacteriophages that specifically infect and eliminate only the antibiotic-resistant bacterial strains carrying particular resistance genes, thereby preserving the rest of the microbiota and avoiding dysbiosis.
Solution Approach 2:
The invention applies local quality by making the antimicrobial action specific to certain bacterial strains rather than uniform across all bacteria. The phages are engineered to target specific antibiotic resistance genes, creating a localized effect that eliminates only the harmful resistant bacteria while leaving beneficial microbiota intact, thus preventing dysbiosis.
2Reliability
If oral gentamicin therapy is administered to decolonize carbapenem-resistant Klebsiella pneumoniae, then the risk of severe infection is reduced, but the microbiota is disrupted causing dysbiosis and selection of additional antibiotic resistance
Solution Approach 1:
The invention converts the harmful effect of antibiotic resistance into a beneficial targeting mechanism. By designing phages that specifically recognize and infect bacteria carrying antibiotic resistance genes, the therapy turns the presence of resistance genes (which normally confer survival advantage) into a vulnerability that allows selective elimination of resistant bacteria without affecting susceptible microbiota.
Solution Approach 2:
The invention introduces bacteriophages as an intermediary between the treatment goal and the target bacteria. Instead of using antibiotics that directly kill bacteria and cause collateral damage, the phages act as mediators that specifically locate, infect, and eliminate only the resistant bacterial strains, thereby achieving decolonization without disrupting the broader microbiota.
3Reliability
If topical treatment with mupirocin is used to decolonize MRSA from the skin, then the risk of MRSA infection is reduced, but the treatment is limited to skin/nose carriage and not effective for intestinal decolonization
Solution Approach 1:
The invention creates a universal decolonization platform based on bacteriophages that can be applied to multiple body sites (skin, nose, intestine) and targeted against different types of antibiotic-resistant bacteria. The phage system is adaptable and can be engineered to recognize various resistance genes, making it a versatile tool that overcomes the limitations of site-specific treatments like mupirocin.
Solution Approach 2:
The invention changes the key parameter of specificity from being location-dependent (as with topical mupirocin) to being gene-dependent (as with engineered phages). By targeting antibiotic resistance genes rather than physical locations, the therapy can be administered systemically and act throughout the body, including the intestine, while maintaining high specificity for resistant bacteria.
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 allows for the selective eradication of antibiotic-resistant bacteria from the intestinal microbiota without disrupting the rest of the microbiota, reducing the risk of infection during medical procedures and minimizing side effects.
Implementation Method 1
engineered bacteriophages or packaged phagemids that specifically target and eliminate antibiotic-resistant bacterial strains by modifying their DNA
Data Source
AI summary
The invention relates to methods, kits, and compositions for reducing the level of or eliminating antimicrobial resistant (AMR) bacteria in situ. The invention encompasses compositions and methods for selectively eradicating antibiotic resistance in bacteria that carry antibiotic resistance genes in the microbiota using packaged phagemids. The microbiota can be intestinal and the packaged phagemids can be administered to a healthy subject or patient, for example, orally, rectally (e.g., in an enema), vaginally, nasally or to the skin. The phagemid encodes a nuclease or other enzyme that genetically modifies the DNA encoding the antibiotic resistance gene so that the bacteria can then be eliminated with the antibiotic.