Morphological study on the antifungal action of voriconazole against Aspergillus fumigatus

Nishiyama Y., Hasumi Y., Yamaguchi H., Abe S.

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Voriconazole (VRCZ) is a new triazole antimycotic that is active against a wide spectrum of pathogenic fungi such as Candida spp, and Aspergillus spp. Recently, VRCZ has been shown to be effective as the primary therapy for invasive aspergillosis. It acts by inhibiting of ergosterol biosynthesis. The morphological consequences of the action of VRCZ on susceptible fungal pathogens have not yet been studied. Therefore, we conducted a morphological study on A. fum igatus in order to gain a better understanding of the mode of action of this drug. A. fumigatus was grown at 30°C in the RPMI 1640 medium with or without VRCZ. For scanning electron microscopy (SEM), fungal cells were fixed with glutaraldehyde and osmium tetroxide, dehydrated in acetone, and freeze-dried in t-butyl alcohol. The dried samples were coated with osmium and examined under a JEOL JSM-6700F. For transmission electron microscopy, cells were fixed with glutaraldehyde and potassium permanganate, dehydrated in acetone, and embedded in Quetol 653. Next, thin sections were stained with uranyl acetate and lead citrate, and observed under a Hitachi H-7000. VRCZ at concentrations of 0.1-1 µg/ml strongly inhibited the in vitro growth of A. fumigatus and induced striking changes in hyphal morphology depending on the drug concentration and the length of the incubation. SEM revealed swelling and deformation of the hypha I tips and formation of short branches from the lateral walls, and finally disruption of the hyphal tips and collapse of whole hyphae. In the thin sections, cell wall thickening, accumulation of electron-dense granules in the cell wall, and disruption of the cytoplasmic membrane and intracellular organelles were observed. These morphological findings of indicate that VRCZ first affects the cytoplasmic membrane and then inhibitis the formation of the cell wall and induces disintegration of cytoplasmic organelles, resulting in a lethal effect.

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17th International Society for Human and Animal Mycology
    • ISHAM 17th (2009)