title: In VitroandIn VivoAntifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection.
abstract: The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range ofin vitroandin vivostudies. PC945 was characterized as a potent, tightly binding inhibitor ofAspergillus fumigatussterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 μM and 0.22 μM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolatedA. fumigatusstrains, the MIC values of PC945 ranged from 0.032 to >8 μg/ml, while those of voriconazole ranged from 0.064 to 4 μg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistantA. fumigatusgrowth yielded IC50(determined based on optical density [OD]) values of 0.0012 to 0.034 μg/ml, whereas voriconazole (0.019 to >1 μg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 μg/ml), includingAspergillus terreus,Trichophyton rubrum,Candida albicans,Candida glabrata,Candida krusei,Cryptococcus gattii,Cryptococcus neoformans, andRhizopus oryzae(1 or 2 isolates each). In addition, whenA. fumigatushyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected withA. fumigatusintranasally, 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.
authors.affiliation: Pulmocide Ltd., London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Colley
authors.affiliation: Institut Pasteur, CNRS, Molecular Mycology Unit, French National Reference Center for Invasive Mycoses & Antifungals, URA3012, Paris, France.|Paris Diderot, Sorbonne Paris Cité University, Paris, France.|Parasitology-Mycology Laboratory, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alanio
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Wales, United Kingdom.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kelly
authors.affiliation: Pulmocide Ltd., London, United Kingdom.
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Sehra
authors.affiliation: Nihon University, Chiba, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kizawa
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Wales, United Kingdom.
authors.forename: Andrew G S
authors.initials: AGS
authors.lastname: Warrilow
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Wales, United Kingdom.
authors.forename: Josie E
authors.initials: JE
authors.lastname: Parker
authors.affiliation: Centre for Cytochrome P450 Biodiversity, Institute of Life Science, Swansea University Medical School, Wales, United Kingdom.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Kelly
authors.affiliation: Nihon University, Chiba, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Kimura
authors.affiliation: Pulmocide Ltd., London, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Anderson-Dring
authors.affiliation: Nihon University, Chiba, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakaoki
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Mihiro
authors.initials: M
authors.lastname: Sunose
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Onions
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Damien
authors.initials: D
authors.lastname: Crepin
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Franz
authors.initials: F
authors.lastname: Lagasse
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Crittall
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shannon
authors.affiliation: Sygnature Discovery Ltd., Nottingham, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Cooke
authors.affiliation: Institut Pasteur, CNRS, Molecular Mycology Unit, French National Reference Center for Invasive Mycoses & Antifungals, URA3012, Paris, France.|Paris Diderot, Sorbonne Paris Cité University, Paris, France.|Parasitology-Mycology Laboratory, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bretagne
authors.affiliation: Compchem Resource, Pendock, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: King-Underwood
authors.affiliation: Pulmocide Ltd., London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Murray
authors.affiliation: Pulmocide Ltd., London, United Kingdom kaz@pulmocide.com.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Pulmocide Ltd., London, United Kingdom.
authors.forename: Pete
authors.initials: P
authors.lastname: Strong
authors.affiliation: Pulmocide Ltd., London, United Kingdom.
authors.forename: Garth
authors.initials: G
authors.lastname: Rapeport
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000302:isolation & purification; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D001549:Benzamides; D005656:Fungal Proteins; C000625812:PC945 compound; D014230:Triazoles; D017964:Itraconazole; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; C465527:cytochrome P-450 CYP51B, Aspergillus; D065819:Voriconazole
keywords: Aspergillus fumigatus; CYP51; azole; azole resistant; inhalation; long acting