Polynucleotide Targeting of Pathogen Repeat Sequences Against Drug Resistance
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Solution Overview
Problem
Nosocomial infections caused by antibiotic-induced pathogens, particularly Clostridium difficile and vancomycin-resistant Enterococcus sp., are difficult to treat due to multi-drug resistance and biofilm formation, leading to high mortality rates and limited treatment options, with existing methods often failing to sustain efficacy as pathogens mutate and develop resistance.
Innovation Solution
A system and method targeting conserved nucleotide repeat sequences and their neighborhood genes on pathogen genomes using engineered polynucleotide constructs, including enzymes to cleave and remove these sequences, ensuring broad-spectrum effectiveness against multiple strains without cross-reactivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibiotics are used to treat infections, then bacterial infections are suppressed, but pathogens develop multi-drug resistance and biofilm formation
Solution Approach 1:
The invention segments the pathogen genome into multiple targetable repeat sequences distributed across different genomic locations. By targeting multiple segmented sites simultaneously rather than a single site, the treatment prevents the pathogen from developing resistance through single mutation events, thereby maintaining treatment efficacy against multi-drug resistant strains
Solution Approach 2:
The invention uses engineered polynucleotide constructs as intermediaries that contain guide sequences complementary to pathogen repeat sequences. These constructs mediate the delivery of therapeutic agents to multiple genomic locations, enabling broad-spectrum targeting while minimizing direct exposure of the pathogen to harsh antibiotics that would select for resistance
2Reliability
If single gene function is targeted in pathogens, then specific pathogen functions are inhibited, but pathogens mutate targets and develop resistance
Solution Approach 1:
Instead of targeting a single gene, the invention segments the target into multiple repeat sequences distributed across the pathogen genome. This segmentation ensures that inhibition of any single repeat sequence does not allow the pathogen to maintain functionality through mutation of one site, as multiple other repeat sequences remain targeted
Solution Approach 2:
The repeat sequences serve as universal targets across different strains of antibiotic-induced pathogens. The engineered polynucleotide constructs are designed with guide sequences that can recognize and bind to these conserved repeat sequences, providing multi-functional targeting capability that maintains therapeutic efficacy across varying pathogen compositions
3Reliability
If antibiotics are administered, then bacterial infections are treated, but beneficial human microbiome is killed
Solution Approach 1:
The invention applies local quality by designing polynucleotide constructs with guide sequences that are specific to pathogen repeat sequences and do not hybridize with commensal or human genomic DNA. This ensures that the therapeutic action is localized to the pathogen genome only, leaving the beneficial microbiome and host genome unaffected
Solution Approach 2:
The engineered polynucleotide constructs act as intermediaries that provide sequence-specific targeting. The guide sequences in these constructs serve as mediators that recognize pathogen-specific repeat sequences through complementary base pairing, enabling selective pathogen targeting without affecting commensal bacteria or human cells
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
Effectively combats antibiotic-induced pathogens by disrupting genetic machinery, reducing relapse, and minimizing side effects, while maintaining treatment efficacy by targeting multiple sites simultaneously.
Implementation Method 1
a first enzyme capable of nicking and cleaving the identified set of nucleotide sequences
Implementation Method 2
a second enzyme capable of removal of a set of neighborhood genes flanking the set of nucleotide repeat sequences
Data Source
AI summary
Nosocomial infections are a major threat to the health sector. A specific category of these are the infections caused by antibiotic induced susceptibility to various pathogenic bacteria. This disclosure relates generally to method and system for combating infections due to antibiotic induced pathogens. The system provides strategies to combat pathogenic infections caused by multi-drug resistant (MDR) and extensively drug resistant (XDR) strains of antibiotic induced pathogens. The idea used in this disclosure utilizes the fact that multiple occurrences of a conserved stretch of nucleotide sequence on a pathogen genome and surrounded by genes encoding virulence factors or which are in vicinity of genes essential for survival of the candidate pathogen can be targeted to disrupt the overall genetic machinery of the pathogen. The present disclosure has been explained on sequenced genomes of Clostridium difficile and vancomycin-resistant Enterococcus sp.