MYCOLab Ai Logo - gold and army green

Improving the production of micafungin precursor FR901379 in Coleophoma empetri using heavy-ion irradiation and its mechanism analysis

Summary

Researchers used heavy-ion radiation to create improved strains of a fungus that produces a precursor to micafungin, an important antifungal drug. The improved strains produced over 3.5 times more of the desired compound than the original strain. By analyzing the genetic changes in these improved strains, the scientists identified which genes were most important for boosting production, helping guide future improvements in manufacturing this life-saving medicine.

Background

Micafungin is a semisynthetic echinocandin antifungal agent derived from FR901379 produced by Coleophoma empetri. The fungus has poor production capacity in biomanufacturing, making it difficult to meet pharmaceutical demands. Heavy-ion irradiation is an emerging mutagenesis technique that has shown promise in filamentous fungi breeding but has not been applied to FR901379 production.

Objective

This study aimed to improve FR901379 production in C. empetri using heavy-ion irradiation mutagenesis and to elucidate the molecular mechanisms underlying high-yield mutants. The researchers sought to understand how DNA damage repair pathways contribute to mutation diversity and production phenotypes.

Results

Two rounds of heavy-ion irradiation produced a mutant (ZZ-138) with FR901379 titre of 1.1 g/L, a 253.7% increase over wild-type. NHEJ-deficient mutants showed higher sensitivity to radiation and greater mutation diversity. Genomic analysis revealed mutations in genes encoding morphological differentiation proteins, oxidoreductases, and transcriptional factors, with upregulation of the core gene mcfA.

Conclusion

Heavy-ion irradiation effectively enhanced FR901379 production through mutations affecting morphological differentiation and metabolic regulation. The study demonstrates that NHEJ-deficient strains generate more diverse mutations, providing a superior mutant library for strain improvement. The high-yield mutants serve as excellent chassis for further metabolic engineering of micafungin production.
  • Published in:Mycology,
  • Study Type:Experimental Study,
  • Source: 10.1080/21501203.2024.2426484, PMID: 40415921
Scroll to Top