MYCOLab Ai Logo - gold and army green

Pathogen Enzyme-Mediated Alkoxyamine Homolysis as a Killing Mechanism of Aspergillus fumigatus

Summary

Researchers have developed a new type of antifungal drug that uses the fungus’s own enzymes against it. The drug is inactive until it encounters an enzyme produced by Aspergillus fumigatus, where it releases toxic molecules that kill the fungus. Importantly, this approach works against both normal and drug-resistant strains of the fungus, offering hope for treating serious fungal infections that don’t respond to current treatments.

Background

Aspergillus fumigatus is a pathogenic fungus causing serious infections in immunocompromised individuals. The emergence of antifungal-resistant strains, particularly to azole drugs, has become a critical public health concern. Current antifungal therapies are limited by resistance mechanisms and adverse side effects.

Objective

To develop a novel antifungal strategy based on enzyme-mediated generation of toxic radical species from alkoxyamine prodrugs activated by pathogen-secreted dipeptidyl peptidase. The study aimed to demonstrate efficacy against both azole-susceptible and azole-resistant A. fumigatus strains.

Results

Synthesized alkoxyamines remained stable in aqueous and organic environments with half-lives exceeding 10 days. Enzymatic activation by dipeptidyl peptidase IV led to homolysis generating toxic alkyl radicals and stable nitroxide. Prodrug Va inhibited growth of both azole-susceptible and azole-resistant A. fumigatus strains in a concentration-dependent manner, with 42% growth inhibition at 10 µg/L.

Conclusion

This work presents a novel chemical strategy for antifungal therapy against A. fumigatus based on pathogen enzyme-mediated generation of toxic radicals. The approach overcomes conventional azole resistance mechanisms and demonstrates efficacy against resistant strains, offering potential for new therapeutic applications in treating invasive aspergillosis.
  • Published in:Journal of Fungi,
  • Study Type:In vitro experimental study,
  • Source: PMID: 40985416, DOI: 10.3390/jof11070503
Scroll to Top