Guanine Riboswitch Binding Compounds for Antibiotic Resistance

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Solution Overview

Problem

Current antibiotic therapies are ineffective against Staphylococcus aureus and Clostridium difficile due to multi-drug resistance, and existing antimicrobial compounds often have non-specific antibacterial activities or are not targeted at essential virulence genes, leading to resistance and toxicity issues.

Innovation Solution

Development of compounds that specifically bind to the guanine riboswitch to inhibit the expression of the guaA gene, essential for survival and virulence in pathogens, preventing ribosylation to avoid broad toxicity and resistance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antibiotics are used to treat S. aureus and C. difficile infections, then initial treatment may be effective, but multi-drug resistance develops leading to treatment failure

Engineering Contradiction:

Improveantibiotic treatment effectivenessVSAvoidtreatment durability

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent changes the target parameter from protein-based antibiotic targets to RNA riboswitch targets. By designing compounds that bind to the guanine riboswitch aptamer region, the invention targets a different molecular parameter (RNA structure) that pathogens have not developed resistance against, thereby maintaining treatment effectiveness and durability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces a new intermediary molecule - the guanine riboswitch-binding compound - that mediates between the administered drug and the essential guaA gene. This intermediary binds specifically to the riboswitch structure, triggering conformational changes that inhibit gene expression without relying on conventional antibiotic mechanisms

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If guanine analogs are used to target the guanine riboswitch, then gene expression can be inhibited, but non-specific antibacterial activity occurs against broad spectrum bacteria including non-pathogenic species

Engineering Contradiction:

Improvegene expression inhibitionVSAvoidnon-specific toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds with specific structural features that match the guanine riboswitch binding pocket in pathogenic bacteria. The compounds contain functional groups positioned to form specific hydrogen bonds and hydrophobic interactions with residues in the S. aureus and C. difficile riboswitches, while lacking the properties needed to bind non-pathogenic bacterial riboswitches, thereby achieving selective toxicity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention segments the antibacterial activity into two distinct components: (1) specific binding to the guanine riboswitch aptamer region through complementary structural features, and (2) selective inhibition of pathogenic bacteria only. This segmentation allows the compound to differentiate between pathogenic and non-pathogenic species, reducing non-specific toxicity while maintaining gene expression inhibition

Inventive Principle:

Principle #1Segmentation

3Reliability

If existing antimicrobial compounds are used, then bacterial growth may be inhibited, but resistance develops and toxicity to host and commensal microorganisms occurs

Engineering Contradiction:

Improveantimicrobial activityVSAvoidresistance and toxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent substitutes the conventional antibiotic mechanism (inhibiting protein synthesis, cell wall formation, or DNA replication) with an RNA-based mechanism. By targeting the guanine riboswitch, a regulatory RNA element, the invention replaces protein-targeting mechanics with RNA-structure-targeting mechanics, creating a fundamentally new mode of action that bypasses existing resistance mechanisms

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 compounds effectively target and inhibit the guaA gene in pathogens, reducing the risk of resistance development and minimizing toxicity to non-targeted bacteria and hosts, offering a selective and specific antimicrobial approach.

Implementation Method 1

Ligand-binding results in structural changes in the riboswitch that affect the ability of the mRNA molecule to be properly transcribed or translated

Methodology Applied

Scientific EffectLigand binding:

Implementation Method 2

Riboswitches are segments of the 5′-untranslated region of certain mRNA molecules that, upon recognition of specific ligands, modify the expression of one or more proteins encoded in the message

Methodology Applied

Scientific EffectRiboswitch structural change:

Data Source

PatentUS9993491B2Guanine riboswitch binding compounds and their use as antibiotics

Publication Date: 2018.06.12 SCOPRA SCI & GENIE SEC

AI summary

The present invention includes novel compounds and pharmaceutically acceptable formulations of said compounds which exhibit antibiotic activity against microorganisms bearing a guanine riboswitch that controls the expression of the guaA gene, including organisms which are resistant to certain antibiotic families, and which are useful as antibacterial agents for treatment or prophylaxis of bacterial infections in animals or in humans, in particular but not limited to infections of the mammary gland, or their use as antiseptics, agents for sterilization or disinfection.