Efficacy of Oral E1210, a New Broad-Spectrum Antifungal with a Novel Mechanism of Action, in Murine Models of Candidiasis, Aspergillosis, and Fusariosis

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmon...

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Published in:Antimicrobial Agents and Chemotherapy 2011-10, Vol.55 (10), p.4543-4551
Main Authors: Hata, Katsura, Horii, Takaaki, Miyazaki, Mamiko, Watanabe, Nao-aki, Okubo, Miyuki, Sonoda, Jiro, Nakamoto, Kazutaka, Tanaka, Keigo, Shirotori, Syuji, Murai, Norio, Inoue, Satoshi, Matsukura, Masayuki, Abe, Shinya, Yoshimatsu, Kentaro, Asada, Makoto
Format: Article
Language:English
Subjects:
Aminopyridines - administration & dosage
Aminopyridines - pharmacology
Aminopyridines - therapeutic use
Amphotericin B
Animal models
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antifungal Agents
Antifungal Agents - administration & dosage
Antifungal Agents - pharmacology
Antifungal Agents - therapeutic use
antifungal properties
Aspergillosis
Aspergillosis - drug therapy
Aspergillosis - microbiology
Aspergillus flavus
Aspergillus flavus - drug effects
Aspergillus fumigatus
Aspergillus fumigatus - drug effects
Biological and medical sciences
biosynthesis
Candida albicans
Candida albicans - drug effects
Candida tropicalis
Candida tropicalis - drug effects
Candidiasis
Candidiasis - drug therapy
Candidiasis - microbiology
Caspofungin
Colony-forming cells
Data processing
drug therapy
Experimental Therapeutics
Female
fluconazole
fungi
Fusariosis
Fusariosis - drug therapy
Fusariosis - microbiology
Fusarium - drug effects
Fusarium solani
Glycosylphosphatidylinositol
Human mycoses
Infection
Infectious diseases
Isoxazoles - administration & dosage
Isoxazoles - pharmacology
Isoxazoles - therapeutic use
Lung
mechanism of action
Medical sciences
Mice
Mice, Inbred ICR
Microbial Sensitivity Tests
Miscellaneous mycoses
Mycoses
Pharmacology. Drug treatments
respiratory tract diseases
Survival
survival rate
Voriconazole
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Summary:E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.00366-11