The profile of PC945, a novel triazole antifungal, designed for administration via inhalation, has been assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tight-binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (IC50, 0.23 μM and 0.22 μM, respectively), with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032∼>8 μg/ml, whilst those of voriconazole ranged from 0.064∼4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth, yielded IC50 (OD) values between 0.0012∼0.034 μg/ml, whereas voriconazole (0.019∼>1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (MIC ranged from 0.0078∼2 μg/ml) including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans andRhizopus oryzae (1∼2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945, and then washed, PC945 was found to be quickly absorbed into both target and non-target cells and to produce persistent antifungal effects. In temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at 14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.
Date of article/Start date of trial:
Monday, March 13, 2017
New antifungal drugs