Inhibitors of chorismate synthase targeting the shikimate pathway

Overview

This research program focuses on developing inhibitors of chorismate synthase (CS), the enzyme that catalyzes the seventh and final step of the shikimate pathway. The shikimate pathway is responsible for the biosynthesis of essential aromatic compounds in prokaryotes, fungi, and plants, but is absent in mammals, making CS an attractive target for antimicrobial and herbicidal applications.

The project has identified structural analogs of 5-enolpyruvyl-shikimate 3-phosphate (EPSP) featuring charged anionic groups around a simple molecular scaffold. Structure-activity relationship (SAR) analysis around the initial hit structure has confirmed inhibitory activity against chorismate synthase, establishing a foundation for further optimization.

Technical specifications

Target and mechanism:

• Chorismate synthase (CS), catalyzing the final step of the shikimate pathway
• Compounds are structural analogs of the natural substrate EPSP
• Charged anionic groups positioned around a simple scaffold to mimic substrate interactions

Research approach:

• Structure-activity relationship (SAR) analysis around the initial hit structure
• Biochemical validation conducted in collaboration with Prof. Peter Macheroux
• Focus on the conserved shikimate pathway present in bacteria, fungi, and plants but absent in mammals

Potential applications:

• Antimicrobial agents targeting bacterial pathogens
• Antifungal compounds
• Herbicides exploiting the plant-specific pathway
• Biochemical research tools for studying aromatic compound biosynthesis

Technology readiness level

The research is at an early discovery stage. Initial hit compounds have been identified and SAR studies have confirmed inhibitory activity against chorismate synthase. The work is being pursued in collaboration with a biochemistry expert. Further validation, including expanded SAR exploration, potency optimization, and biological efficacy testing, is needed to advance these compounds toward practical applications.