Thiourea Derivatives Reversing Multidrug Resistance in Staphylococcus aureus

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The rising incidence of multidrug-resistant Staphylococcus aureus infections poses a significant threat due to the rapid development of antimicrobial resistance, necessitating the discovery of new antimicrobial agents that can effectively inhibit the growth of these resistant bacteria and reverse multidrug resistance mechanisms.

Innovation Solution

Thiourea derivatives, specifically compounds I and II, are developed to inhibit the growth of multidrug-resistant Staphylococcus aureus by altering membrane potential, blocking efflux pumps, and inducing the production of reactive oxygen species, thereby enhancing the sensitivity of bacteria to antibiotics and reversing multidrug resistance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antibiotics are used to treat bacterial infections, then treatment effectiveness is maintained against susceptible bacteria, but treatment fails against multidrug-resistant Staphylococcus aureus strains

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidbacterial resistance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the antibacterial action into two distinct components: (1) thiourea derivatives that specifically target and inhibit efflux pump function, and (2) conventional antibiotics that provide the primary bactericidal effect. This segmentation allows each component to perform its specialized function, with the thiourea derivative preventing drug expulsion and the antibiotic delivering the lethal blow to the bacteria.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The thiourea derivative acts as an intermediary substance that mediates between the conventional antibiotic and the resistant bacteria. It binds to the efflux pump proteins, blocking their ability to expel the antibiotic, thereby enabling the antibiotic to accumulate to effective concentrations inside the bacterial cell without requiring modification of the antibiotic itself.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Adaptability or versatility

If new antimicrobial agents are developed to overcome resistance, then treatment options expand, but development time and resource requirements increase

Engineering Contradiction:

Improvetreatment optionsVSAvoiddrug development time

Core Design Contradiction:

Adaptability or versatilityVSLoss of time

Solution Approach 1:

The thiourea derivatives perform a preliminary action by pre-blocking the efflux pump mechanisms before the antibiotic is administered. This preliminary inhibition of resistance mechanisms allows subsequently administered conventional antibiotics to work effectively, eliminating the need to wait for entirely new antibiotic classes to be developed and tested.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent changes the pharmacological parameters of existing antibiotic treatments by introducing thiourea derivatives that alter the intracellular concentration dynamics of antibiotics. This parameter change (increasing intracellular antibiotic accumulation) transforms the effectiveness profile of conventional antibiotics against resistant strains without requiring development of new molecular entities.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If higher doses of antibiotics are administered to overcome resistance, then bacterial killing effect increases, but side effects and toxicity increase

Engineering Contradiction:

Improvebacterial killing effectVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The thiourea derivative serves as an intermediary that enables lower doses of antibiotics to achieve higher intracellular concentrations by blocking efflux. This intermediary action allows the system to achieve the desired bacterial killing effect at lower external drug concentrations, thereby reducing systemic exposure and potential side effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

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

Compounds I and II demonstrate significant inhibitory activity against multidrug-resistant Staphylococcus aureus strains, reducing the minimum inhibitory concentrations of antibiotics by up to thousand folds when used in combination, effectively reversing multidrug resistance and increasing bacterial sensitivity, thus offering a promising treatment for latent infections.

Implementation Method 1

altering membrane potential

Methodology Applied

Scientific EffectMembrane potential alteration:

Implementation Method 2

blocking efflux pumps

Methodology Applied

Scientific EffectEfflux pump inhibition:

Implementation Method 3

inducing the production of reactive oxygen species

Methodology Applied

Scientific EffectReactive oxygen species production: Oxidation

Data Source

PatentUS9387186B2Thiourea derivatives

Publication Date: 2016.07.12 CHOUDHARY MUHAMMAD IQBAL

AI summary

Two thiourea derivatives N-(3-chlorophenyl)-N′-(3,4-difluorophenyl)thiourea and N-(3-chlorophenyl)-N-(3-methoxyphenyl)-thiourea are reported as treatment of multidrug resistance infections from Staphylococcus aureus.