Exposure of Aspergillus fumigatus to caspofungin results in the release, and de novo biosynthesis, of gliotoxin

Abstract

Caspofungin is a member of the echinocandin class of antifungal agents that inhibit the synthesis of β 1,3 glucan thus disrupting fungal cell wall structure and function. Exposure of the Aspergillus fumigatus cultures to caspofungin (0.01, 0.1 or 1.0 μg/ml) resulted in a reduction in cell growth, but the production of the epipolythiodioxopiperazine toxin, gliotoxin, was comparable, or greater, in cultures exposed to caspofungin than untreated controls. Exposure of A. fumigatus hyphae to 1.0 μg/ml caspofungin for 4 h resulted in the release of amino acids (P = 0.01), protein (P = 0.002) and gliotoxin (P = 0.02). Cultures of A. fumigatus incubated in the presence of caspofungin for 4 or 24 h demonstrated enhanced gliotoxin release (P = 0.04 and 0.03, respectively) and biosynthesis (P = 0.04 and 0.03, respectively) compared to that by control cultures. The results presented here indicate that exposure of A. fumigatus to caspofungin results in increased cell permeability and an increase in the synthesis and release of gliotoxin. Since gliotoxin has well established immunosuppressive properties it is possible that exposure of A. fumigatus to caspofungin may potentiate the production of this toxin at the site of infection. Elevated gliotoxin biosynthesis may be an attempt by the fungus to restore the redox balance of the cell following exposure to the antifungal agent but the overall effect appears to be enhanced synthesis and release.