ClbP-Activated Prodrug Antibiotics for Selective E. coli Killing
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Solution Overview
Problem
Colibactin-producing E. coli strains are associated with conditions such as colitis, irritable bowel syndrome, and colorectal cancer, and existing treatments are inadequate in selectively targeting and eliminating these bacteria without harming other strains of E. coli.
Innovation Solution
Development of prodrug antibiotics that are selectively activated by the ClbP peptidase in colibactin-producing E. coli, converting to active drugs that kill these bacteria while sparing others, and potentially used in combination with chemotherapy for treating colorectal cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibiotics are used to treat colibactin-producing E. coli, then the bacteria can be killed, but other strains of E. coli and gut microbiome are harmed
Solution Approach 1:
The prodrug antibiotic is designed with a specific chemical structure that allows it to be activated only by the ClbP peptidase enzyme present in colibactin-producing E. coli strains. This creates local specificity where the antibiotic only exerts its toxic effect in bacteria that possess the activating enzyme, thereby selectively killing colibactin-producing strains while sparing other E. coli strains and maintaining gut microbiome diversity.
Solution Approach 2:
The ClbP peptidase enzyme serves as an intermediary that converts the inactive prodrug form into the active antibiotic form. This intermediary mechanism ensures that the antibiotic is only activated and becomes toxic within colibactin-producing E. coli cells, providing a built-in selection mechanism that prevents harm to other bacterial strains.
2Reliability
If broad-spectrum antibiotics are used to eliminate colibactin-producing E. coli, then cancer prevention can be achieved, but the gut microbiome balance is disrupted
Solution Approach 1:
The prodrug antibiotic exhibits local quality by being selectively activated only in colibactin-producing E. coli strains through the ClbP peptidase enzyme. This ensures that the antibiotic action is confined specifically to bacteria that produce colibactin, a key driver of colorectal cancer, while leaving other beneficial gut microbiota unaffected and maintaining overall microbiome stability.
Solution Approach 2:
The patent converts the harmful ClbP peptidase enzyme, which activates colibactin toxin, into a beneficial selector. By designing the prodrug antibiotic to be activated specifically by ClbP, the enzyme that was previously part of the harmful toxin production pathway is now harnessed as a selective activation mechanism, turning a harmful factor into a beneficial selection criterion for cancer prevention.
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 prodrug antibiotics effectively target and eliminate colibactin-producing E. coli, preventing colorectal cancer initiation and treating associated conditions, while maintaining the balance of the gut microbiome.
Implementation Method 1
This gets converted to the active colibactin by a dedicated peptidase (ClbP) just before release from the bacteria to prevent autotoxicity
Data Source
AI summary
The present disclosure provides methods of preventing colorectal cancer and/or killing colibactin-producing E. coli. Also provided are prodrug antibiotics suitable for preventing colorectal cancer and/or killing colibactin-producing E. coli, and methods of making prodrug antibiotics. Various prodrug antibiotics may be used. For example, a prodrug antibiotic may be:or any combination thereof, wherein R is a substituted or unsubstituted aliphatic group. In various examples, the prodrug antibiotic may be a salt or in the form of a composition.