Chemical validation of fungal SUMO conjugation inhibition as a fungicide target

Overview

This research program aims to chemically validate the SUMOylation pathway as a novel target for fungicide development. SUMOylation is an essential post-translational modification found in eukaryotes, including phytopathogenic fungi. Previous genetic studies have demonstrated that SUMO plays a critical role in fungal growth, conidiation, sexual development, and DNA damage tolerance, making it a promising target for crop protection. The project leverages a recently available family of SUMOylation inhibitors originally developed as anti-cancer drugs to test whether chemical inhibition of fungal SUMOylation can suppress fungal growth, using Botrytis cinerea as a proof-of-concept pathogen.

The broader vision is to establish a fungicide discovery program targeting species-specific protein-protein interactions within the SUMOylation machinery, with the potential to deliver highly selective fungicides that minimize off-target effects.

Technical specifications

Research approach:

• Chemical inhibition of SUMOylation using commercially available inhibitors whose mechanism of action is conserved in fungal systems
• Proof-of-concept testing on Botrytis cinerea, a major phytopathogen
• Dose-response assays with five dilution series per pathogen-product combination, using a commercial fungicide as positive control
• Monitoring of spore germination (minimum N=50 randomly counted spores) and relative inhibition of mycelial growth, calculated as 100×[1 - proportion of radial colony growth relative to control]
• Estimation of LD50 and LD95 critical values from experimental data
• Target engagement analysis conducted in collaboration with Dr. Maria Lois
• Expected project duration: 9-12 months

Scientific rationale:

• Genetic validation in Aspergillus nidulans shows SUMO is required for hyphal growth, conidiation, sexual development, and DNA damage tolerance
• Knockout mutants in Aspergillus flavus SUMO gene display defects in conidia formation, aflatoxin production, and host colonization
• Biochemical studies have identified species-specific protein-protein interaction platforms within SUMOylation, supporting the feasibility of developing selective inhibitors

Technology readiness level

This program is at an early-stage research and validation phase. The target (fungal SUMOylation) has been genetically validated in model fungi, and chemical tool compounds are commercially available. The current project represents the critical step of chemically validating the target in a relevant phytopathogen. Success in these proof-of-concept experiments would establish the foundation for a dedicated fungicide discovery program targeting species-specific protein-protein interactions in the SUMOylation pathway.