In Vitro and In Vivo Efficacy of a Novel and Long Acting Fungicidal Azole, PC1244 on Aspergillus fumigatus Infection [PublishAheadOfPrint]

The antifungal effects of the novel triazole, PC1244, designed for topical or inhaled administration, against A. fumigatus have been tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (N=96) with a MIC range of 0.016--0.25 μg/ml, whereas the MIC range for voriconazole was 0.25--0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with an IC₅₀ of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC ranged from <0.0078~2 μg/ml), especially on Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans and Rhizopus oryzae. PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (MFC, 2 μg/ml), which was 8-fold more potent than voriconazole. In vivo, once daily intranasal administration of PC1244 (3.2 ~ 80μg/mL) to temporarily neutropenic, immunocompromised mice 24h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced fungal load in the lung, galactomannan in serum and circulating inflammatory cytokines. Furthermore, 7 days extended prophylaxis with PC1244 showed superior in vivo effects when compared against 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.

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