Engineered Microorganisms with Modified PKS Island
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Solution Overview
Problem
There is a significant unmet need for engineered microorganisms that reduce the potentially deleterious effects of colibactin while maintaining its beneficial effects, as colibactin-producing microorganisms can induce both harmful and beneficial outcomes, such as chromosomal instability and anti-inflammatory effects.
Innovation Solution
An engineered microorganism with a modified pks island, which includes deletions or modifications in clb genes, is developed to produce reduced levels of colibactin, thereby minimizing harmful effects while retaining therapeutic benefits, such as producing therapeutic molecules like phenylalanine metabolizing enzymes or oxalate catabolism enzymes to treat conditions like PKU and hyperoxaluria.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the pks genomic island is retained in the microorganism, then anti-inflammatory and other beneficial effects are maintained, but genotoxicity and chromosomal instability are induced
Solution Approach 1:
The patent extracts and removes specific genes (clbA, clbB, clbC, clbH, clbI, clbJ, clbK, clbL, clbM, clbN, clbO, clbP, clbQ, clbR) from the pks genomic island while retaining the clbS gene. This selective extraction eliminates the assembly line required for colibactin synthesis (thereby removing genotoxicity) while preserving the pks island structure that mediates anti-inflammatory effects.
Solution Approach 2:
The patent segments the pks genomic island by dividing it into functional components: the colibactin synthesis genes (clbA-clbR) are separated from the regulatory and structural elements (including clbS). This segmentation allows independent control of toxic versus beneficial functions.
2Productivity
If colibactin production is maintained, then bacterial growth and maintenance are promoted, but chromosomal instability and DNA damage occur
Solution Approach 1:
The patent converts the harmful colibactin production function into a beneficial or neutral state by deleting the synthesis genes. The pks island is repurposed to provide anti-inflammatory effects without generating DNA-damaging colibactin, effectively transforming a harmful function into a therapeutic one.
3Object-affected harmful factors
If the pks genomic island is modified to reduce colibactin production, then genotoxicity is minimized, but potentially beneficial effects may be reduced
Solution Approach 1:
The patent applies local quality modification by specifically altering the colibactin synthesis genes (clbA-clbR) within the pks island while leaving other regions (particularly clbS and regulatory elements) intact. This localized modification ensures that only the toxic function is eliminated while therapeutic functions are preserved.
Data Source
AI summary
The present invention relates to engineered microorganisms, wherein the engineered microorganisms comprise a therapeutic molecule and a modified pks island.