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© A. Alanio, E. Perret
Prolifération de Cryptococcus neoformans dans des macrophages murins.
Publication : Antimicrobial agents and chemotherapy

In vitro and in vivo antifungal profile of a novel and long acting inhaled azole, PC945, on Aspergillus fumigatus infection

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Antimicrobial agents and chemotherapy - 21 Feb 2017

Colley T, Alanio A, Kelly SL, Sehra G, Kizawa Y, Warrilow AG, Parker JE, Kelly DE, Kimura G, Anderson-Dring L, Nakaoki T, Sunose M, Onions S, Crepin D, Lagasse F, Crittall M, Shannon J, Cooke M, Bretagne S, King-Underwood J, Murray J, Ito K, Strong P, Rapeport G

Link to Pubmed [PMID] – 28223388

Antimicrob. Agents Chemother. 2017 Feb;

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.

https://www.ncbi.nlm.nih.gov/pubmed/28223388