Mitomycin C and Cisplatin DNA Crosslinking Against Bacterial Persisters
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Solution Overview
Problem
Current antibiotics are ineffective against persister cells, which are a significant challenge in treating bacterial infections due to their high tolerance and presence in biofilms, leading to recalcitrant infections and biofilm-related issues.
Innovation Solution
The use of mitomycin C (MMC) or cisplatin, or their derivatives, to directly damage bacterial cells by creating DNA crosslinks, effectively reducing or eradicating persister cells and dormant viable but non-culturable cells, including those in biofilms and wounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional antibiotics are used to treat bacterial infections, then actively growing cells are killed, but persister cells remain tolerant and cause recalcitrant infections
Solution Approach 1:
The patent changes the chemical parameters of the treatment by using mitomycin C and cisplatin instead of traditional antibiotics. These compounds work through different mechanisms (DNA crosslinking) that are effective against metabolically inactive persister cells, thereby resolving the contradiction between reliability against persisters and productivity of killing
Solution Approach 2:
The patent introduces mitomycin C and cisplatin as intermediary substances that mediate the killing of persister cells. These compounds serve as a bridge between the treatment goal and the resistant target population, enabling effective eradication where traditional antibiotics fail
2Reliability
If antibiotics are administered to clear bacterial infections, then growing cells are eliminated, but persister cells survive and lead to treatment failure
Solution Approach 1:
The patent converts the harmful persistence mechanism into a benefit by using compounds that specifically target dormant cells. The metabolic inactivity that protects persisters from antibiotics becomes the very condition that makes them susceptible to mitomycin C and cisplatin, turning the persistence advantage into a vulnerability
3Reliability
If new antibiotics are discovered to target persister cells, then treatment effectiveness improves, but few distinctly new antibiotics have been discovered recently
Solution Approach 1:
The patent applies the universality principle by using mitomycin C and cisplatin, which are established compounds with known mechanisms of action. These compounds serve multiple functions: they are already FDA-approved, have well-characterized safety profiles, and effectively target persister cells, thereby eliminating the need for extensive new drug development while improving treatment reliability
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
MMC and cisplatin demonstrate broad-spectrum activity against persister cells, achieving greater reduction or eradication compared to traditional antibiotics, without causing biofilm dispersal, and are effective against both growing and non-growing cells, including those in anaerobic conditions.
Implementation Method 1
The use of mitomycin C (MMC) or a derivative thereof, or cisplatin or a derivative thereof, or a combination of MMC or a derivative thereof and cisplatin and a derivative thereof to directly damage bacterial cells by creating DNA crosslinks
Data Source
AI summary
The present disclosure provides a method for killing persister cells with mitomycin C and/or cisplatin, or derivatives thereof. Recalcitrant infections are difficult to treat due to persister cells, a subpopulation of all bacterial populations that is highly tolerant against all traditional antibiotics since the cells are dormant and antibiotics are designed to kill growing cells. Here, we show that MMC and cisplatin eradicate persister cells through a growth-independent mechanism, cross-linking DNA. We find both agents are effective against both planktonic cultures and highly robust biofilm cultures for a broad range of bacterial species, including commensal Escherichia coli K-12 as well as pathogenic species of E. coli, Staphylococcus aureus, and Pseudomonas aeruginosa. In certain approaches cisplatin is superior to MMC.