CMP-KDN Analog Inhibition of Gonococcal LOS Sialylation

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Neisseria gonorrhoeae has developed resistance to almost every conventional antibiotic, necessitating the need for novel therapeutics and vaccines, and existing CMP-NulO compounds may not provide efficient treatment or prevention with low toxicity.

Innovation Solution

Development of cytidine 5'-monophospho-nonulosonate (CMP-NulO) analog compounds, specifically CMP-3-deoxy-D-glycero-D-galacto-nonulosonic acid (CMP-KDN), which serves as a substrate for gonococcal LOS sialyltransferase, potentially reducing virulence and transmission of Neisseria gonorrhoeae by modulating factor H binding and complement activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antibiotics are used to treat Neisseria gonorrhoeae infection, then treatment effectiveness is maintained initially, but bacterial resistance develops leading to treatment failure

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidbacterial resistance

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention changes the chemical parameter of the therapeutic agent from conventional antibiotics to CMP-NulO analog compounds. These analogs mimic the natural substrate CMP-Neu5Ac but with modified nonulosonate structures (such as CMP-KDN, CMP-Dhfn, CMP-Fuc, CMP-Gal, CMP-Glc, CMP-Man, CMP-NANA, CMP-Neu5Gc, CMP-Pse, CMP-Leg, CMP-Rha, CMP-Xyl) that bacteria cannot naturally process, thereby avoiding resistance development while maintaining therapeutic effectiveness against Neisseria gonorrhoeae

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The CMP-NulO analog compounds act as intermediary molecules that compete with the natural substrate CMP-Neu5Ac for binding to the sialyltransferase enzyme Lst in Neisseria gonorrhoeae. By serving as false intermediaries, these analogs inhibit bacterial LOS sialylation without being metabolized by bacterial enzymes, thus preventing treatment resistance while disrupting essential bacterial pathogenesis mechanisms

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If existing CMP-NulO compounds are used for treatment, then some therapeutic effect is achieved, but treatment efficiency and toxicity profile are insufficient

Engineering Contradiction:

Improvetherapeutic effectVSAvoidtreatment efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention applies local quality by selecting specific CMP-NulO analogs with particular sugar moieties (KDN, Dhfn, Fuc, Gal, Glc, Man, NANA, Neu5Gc, Pse, Leg, Rha, Xyl) that exhibit different biological properties. Each analog has tailored local chemical characteristics that optimize its ability to inhibit LOS sialylation while minimizing toxicity, allowing selection of the most effective compound for specific clinical scenarios

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention optimizes treatment efficiency by changing the chemical structure parameters of CMP-NulO compounds. The analogs differ in their nonulosonate sugar components, which affects their affinity for bacterial sialyltransferase, metabolic stability, and toxicity profile. This parameter optimization enables selection of compounds with superior therapeutic indices compared to existing CMP-NulO agents

Inventive Principle:

Principle #35Parameter changes

3Reliability

If LOS sialylation is enhanced to protect Neisseria gonorrhoeae from complement, then bacterial survival increases, but potential therapeutic targets are created

Engineering Contradiction:

Improvebacterial survivalVSAvoidtherapeutic vulnerability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention converts the harmful effect of LOS sialylation (which protects bacteria from complement) into a therapeutic benefit. By using CMP-NulO analogs that inhibit the sialylation process, the treatment exploits the bacteria's dependence on this modification for survival. The analogs transform the protective sialylation mechanism into a vulnerability by blocking the enzymatic pathway required for LOS sialylation, thereby enhancing bacterial susceptibility to complement-mediated killing

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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

CMP-KDN analogs demonstrate efficacy in reducing bacterial burden and modulating immune evasion mechanisms, offering a novel prophylactic or treatment strategy against antibiotic-resistant Neisseria gonorrhoeae infections with potential for low toxicity due to its presence in human tissues.

Implementation Method 1

CMP-KDN serves as a substrate for gonococcal LOS sialyltransferase, enabling incorporation of KDN onto gonococcal lacto-N-neotetraose lipooligosaccharide

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 2

KDN incorporation onto gonococcal lacto-N-neotetraose lipooligosaccharide modulates factor H binding

Methodology Applied

Scientific EffectMolecular binding: Absorption (physical)

Data Source

PatentEP3337488B1Treatment and prevention of neisseria gonorrhoeae infection using CMP-activated nonulosonate analog compounds

Publication Date: 2024.12.18 NAT RES COUNCIL OF CANADA

Figure 1A~1B
Figure 2A~2B
Figure 3A~3B

AI summary

There is provided a method for treating or preventing a Neisseria gonorrhoeae infection in a subject, comprising administering to the subject an effective amount of a compound of general formula I below or a pharmaceutical composition comprising said compound, or a derivative thereof, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, or a stereoisomer thereof.