Novel effect of voriconazole on conidiation of Aspergillus species

Our previous studies of Aspergillus fumigatus showed that colonies that grew in the presence of voriconazole (VCZ) were characteristically white without pigmentation. We therefore investigated the effect of various triazoles on conidiation and pigmentation in four commonly isolated Aspergillus species and the results were compared with those obtained for polyene and echinocandin classes of antifungal drugs. Aspergillus cultures were grown on Sabouraud dextrose agar containing subinhibitory concentrations of the antifungal drugs; fungal colonies that grew in the presence of drug were examined microscopically for conidiation and the number of conidia per fungal colony was determined by haemocytometry. Voriconazole at 0.125-0.5 mg/l inhibited conidiation in A. fumigatus, Aspergillus flavus, Aspergillus niger and Aspergillus nidulans producing white colonies. The effect of voriconazole was concentration dependent and greater than 99% inhibition of conidiation was obtained in A. flavus at 0.5 mg/l. When the white colonies were subcultured on drug-free medium, they readily produced conidia and pigmentation indicating that the effect is reversible. Other triazoles such as itraconazole (ITZ) and posaconazole (PCZ) were poor inhibitors of conidiation. On the other hand, ravuconazole (RCZ) with structural similarity to voriconazole inhibited conidiation in A. fumigatus and A. flavus, but not in A. niger and A. nidulans. Amphotericin B (AMB), nystatin (NYS), caspofungin (CFG) and micafungin (MFG) showed no effect on conidiation. Varying ability among the triazoles to inhibit conidiation in Aspergillus species suggests that the mechanism of action may be unrelated to the well-known inhibition of p450-dependent 14alpha-sterol demethylase, and perhaps is due to direct or indirect effect on the formation of conidia.