In VitroandIn VivoEfficacy of a Novel and Long-Acting Fungicidal Azole, PC1244, onAspergillus fumigatusInfection
ABSTRACTThe antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, againstAspergillus fumigatuswere tested in a range ofin vitroandin vivostudies. PC1244 demonstrated potent antifungal activities against clinicalA. fumigatusisolates (n= 96) with a MIC range of 0.016 to 0.25 μg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinantA. fumigatusCYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis inA. fumigatuswith a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 μg/ml), especiallyAspergillus terreus,Trichophyton rubrum,Candida albicans,Candida glabrata,Candida krusei,Cryptococcus gattii,Cryptococcus neoformans, andRhizopus oryzae. PC1244 also proved to be quickly absorbed into bothA. fumigatushyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 μg/ml) which indicated that it was 8-fold more potent than voriconazole.In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 μg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptibleA. fumigatussubstantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showedin vivoeffects superior to those of 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 ofA. fumigatusinfection in the lungs of humans.