Comparative Analysis of the Aspergillus fumigatus Cell Wall Modifcation and Ensuing Human Dendritic Cell Responses by β‐(1,3)‐Glucan Synthase Inhibitors—Caspofungin and Enfumafungin
Author:
Karine Guilloux · Pushpa Hegde · Sarah Sze Wah Wong ·
Vishukumar Aimanianda · Jagadeesh Bayry · Jean‐Paul Latgé
Date: 20 September 2024
Abstract:
Caspofungin, a lipopeptide, is an antifun- gal drug that belong to the class of echinocandin. It inhibits fungal cell wall β-(1,3)-glucan synthase activ- ity and is the second-line of drug for invasive asper- gillosis, a fatal infection caused mainly by Aspergil- lus fumigatus. On the other hand, Enfumafungin is a natural triterpene glycoside also with a β-(1,3)-glucan synthase inhibitory activity and reported to have anti- fungal potential. In the present study, we compared the growth as well as modifcations in the A. fumig- atus cell wall upon treatment with Caspofungin or Enfumafungin, consequentially their immunomodula- tory capacity on human dendritic cells. Caspofungin initially inhibited the growth of A. fumigatus, but the efect was lost over time. By contrast, Enfumafungin inhibited this fungal growth for the duration investi- gated. Both Caspofungin and Enfumafungin caused a decrease in the cell wall β-(1,3)-glucan content with a compensatory increase in the chitin, and to a minor extent they also afected cell wall galactose content. Treatment with these two antifungals did not result in the exposure of β-(1,3)-glucan on A. fumigatus mycelial surface. Enzymatic digestion suggested a modifcation of β-(1,3)-glucan structure, specifcally its branching, upon Enfumafungin treatment. While there was no diference in the immunostimulatory capacity of antifungal treated A. fumigatus conidia, alkali soluble-fractions from Caspofungin treated mycelia weakly stimulated the dendritic cells, pos- sibly due to an increased content of immunosuppres- sive polysaccharide galactosaminogalactan. Overall, we demonstrate a novel mechanism that Enfuma- fungin not only inhibits β-(1,3)-glucan synthase activ- ity, but also causes modifcations in the structure of β-(1,3)-glucan in the A. fumigatus cell wall.
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