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Discovery of the antifungal compound ilicicolin K through genetic activation of the ilicicolin biosynthetic pathway in Trichoderma reesei

Summary

Scientists used genetic engineering to activate a dormant gene cluster in the fungus Trichoderma reesei, enabling it to produce the antifungal compound ilicicolin H in high quantities. During this process, they discovered a new related compound called ilicicolin K that shows even stronger antifungal properties. These compounds could potentially overcome limitations of current antifungal treatments, especially against drug-resistant fungi like Candida auris.

Background

Ilicicolin H is a potent antifungal compound discovered in 1971 that specifically inhibits the fungal cytochrome bc1 complex. Despite its antifungal efficacy, ilicicolin H shows limited in vivo efficacy due to high plasma protein binding. The ilicicolin H biosynthetic gene cluster is silent under standard cultivation conditions in many fungi.

Objective

The study aimed to activate the silent ilicicolin H biosynthetic gene cluster in Trichoderma reesei by genetically overexpressing the transcription factor TriliR, and to characterize the resulting biosynthetic pathway and products using multi-omics approaches.

Results

BGC activation successfully produced high yields of ilicicolin H in the mycelium (1.34 µg per mg). Molecular networking revealed a novel ilicicolin compound, ilicicolin K, with molecular formula C27H29NO5 that differs from ilicicolin H by a second hydroxylation and additional intramolecular ether bridge formation. Ilicicolin K showed strong antifungal activity against Saccharomyces cerevisiae and moderate activity against Candida auris.

Conclusion

By activating the silent BGC in T. reesei, a high-yielding strain producing both ilicicolin H and the novel ilicicolin K was obtained. The different bioactive properties of these compounds suggest ilicicolin K may overcome limitations of ilicicolin H, particularly regarding drug resistance in fungal pathogens.
  • Published in:Biotechnol Biofuels Bioprod,
  • Study Type:Experimental Research Study,
  • Source: PMC11895301, PMID: 40069746, 10.1186/s13068-025-02628-3
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