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Carabrone inhibits Gaeumannomyces tritici growth by targeting mitochondrial complex I and destabilizing NAD⁺/NADH homeostasis

Summary

Researchers identified how carabrone, a natural compound from plants, kills a fungus that causes wheat disease. The compound works by blocking a key energy-producing system (complex I) inside the fungus’s cells, which prevents it from producing enough energy to survive. This discovery is important because many current fungicides are losing effectiveness due to resistance, and this compound offers a new way to attack fungi. The findings could help develop new and more effective fungicides for protecting crops.

Background

Excessive use of commercial fungicides has led to escalating drug resistance in phytopathogens. Plant secondary metabolites serve as natural chemical defenses and offer promising scaffolds for developing innovative crop protection approaches. Carabrone, a natural sesquiterpene lactone, exhibits antifungal activity but its precise molecular target remains elusive.

Objective

To elucidate the antifungal mechanism of carabrone against Gaeumannomyces tritici through integrated multi-omics analyses and establish its molecular target for development of novel fungicides.

Results

Carabrone suppresses the oxidative phosphorylation pathway and disrupts nicotinate/nicotinamide metabolism, reducing NAD⁺/NADH ratio. ABPP identified 56 mitochondrial carabrone-binding proteins enriched in electron transfer and NAD-related oxidoreductase activities. Comprehensive validation demonstrated carabrone specifically inhibits mitochondrial respiratory chain complex I with an IC₅₀ of 666.53 nM, destabilizing NAD⁺/NADH homeostasis.

Conclusion

This study first establishes mitochondrial complex I as the direct antifungal target of carabrone, revealing its mechanism of action through complex I inhibition that blocks NADH oxidation, induces oxidative stress, and collapses energy metabolism. Scndi1 is validated as a critical tool for screening and validating complex I-targeted fungicides, providing both a lead scaffold and systematic framework for antifungal agent development.
  • Published in:PLoS Pathogens,
  • Study Type:Experimental Research Study,
  • Source: PMID: 41042831, DOI: 10.1371/journal.ppat.1013567
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