Substituted Hydroxamic Acid Compounds Targeting LpxC Enzyme

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Solution Overview

Problem

There is a growing concern of antimicrobial resistance, particularly in Gram-negative bacterial infections, where existing antibacterials are ineffective against multiple-resistant strains, necessitating new antibacterials with novel mechanisms of action.

Innovation Solution

Development of substituted hydroxamic acid compounds that inhibit UDP-3-O-(R-3-hydroxydecanoyl)-N-acetylglucosamine deacetylase (LpxC), an enzyme essential for Gram-negative bacteria, to treat infections such as Neisseria gonorrhoeae by targeting the enzyme's enzymatic activity and overcoming resistance mechanisms.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing antibacterials are used to treat Gram-negative bacterial infections, then treatment of susceptible bacteria is effective, but treatment fails against multiple-resistant strains

Engineering Contradiction:

Improveeffectiveness against bacterial infectionsVSAvoideffectiveness against resistant strains

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent changes the chemical structure parameters of hydroxamic acid compounds to create new molecular entities with altered binding characteristics to LpxC enzyme, enabling activity against resistant strains while maintaining efficacy against susceptible bacteria

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention segments the antibacterial activity from existing drug classes by targeting a completely different enzyme (LpxC) in the lipid A biosynthesis pathway, rather than targeting conventional bacterial targets, thus overcoming cross-resistance

Inventive Principle:

Principle #1Segmentation

2Adaptability or versatility

If new antibacterials with novel mechanisms of action are developed, then effectiveness against resistant strains is improved, but development complexity and time increase

Engineering Contradiction:

Improveeffectiveness against resistant strainsVSAvoiddevelopment complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The hydroxamic acid compounds exhibit universal activity against multiple Gram-negative bacterial species and resistant strains by targeting the conserved LpxC enzyme, which is essential for lipid A biosynthesis across Gram-negative bacteria, thereby achieving broad-spectrum efficacy through a single mechanism

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If LpxC enzyme is targeted to inhibit lipid A synthesis, then bacterial growth is inhibited and antibiotic resistance is overcome, but specificity and potential off-target effects must be managed

Engineering Contradiction:

Improveantibacterial efficacyVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent optimizes local chemical properties of the hydroxamic acid compounds at specific molecular positions to enhance binding affinity and selectivity for LpxC enzyme, thereby improving antibacterial efficacy while minimizing off-target effects through precise molecular design

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS10189786B2Antibacterial compounds

Publication Date: 2019.01.29 THE UNIV OF NORTH CAROLINA AT CHAPEL HILL

AI summary

Disclosed are compounds of formulae (I) and (II) and pharmaceutically acceptable salts thereof, wherein the variables, R, R1, R2, R3, Y, Z, X, R12, R17, R18, R19, Y1, Z1, X1, and X2 are defined herein. These compounds are useful for treating Gram-negative bacteria infections, such as Neisseria gonorrhoeae bacterial infections.