Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis

Abstract

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.

Fig. 1.

Chemical structure of E1210.

Fig. 2.

Comparative efficacies of E1210 and fluconazole in a murine oropharyngeal candidiasis model. Mice, immunosuppressed with cortisone acetate administered subcutaneously 1 day before and 3 days after infection, were orally infected with 4 × 10⁵ CFU of Candida albicans. E1210 was orally administered twice daily and fluconazole was orally administered once daily for three consecutive days starting 3 days after infection. The oral cavity of each mouse was thoroughly swabbed, and the recovered cells were cultured on SDA plates. After incubation at 35°C overnight, the viable cells were counted and expressed as the number of CFU. The viable cell counts were performed in duplicate. *, P < 0.05 versus control (one-way ANOVA with the Dunnett multiple-comparison test).

Fig. 3.

Efficacy of E1210 compared to that of reference antifungals in a murine model of disseminated candidiasis caused by C. albicans IFM49971. Mice (n = 9) were immunosuppressed with 5-FU administered subcutaneously 6 days prior to infection and then intravenously infected with 0.8 × 10⁴ CFU of Candida albicans. E1210 was administered orally twice daily, fluconazole was administered orally once daily, and liposomal amphotericin B or caspofungin was administered intravenously once daily for three consecutive days starting 1 h after infection. The survival rate and survival period were determined over 14 days. (A) E1210; (B) fluconazole; (C) caspofungin; (D) liposomal amphotericin B. *, P < 0.05 versus control group (log rank test with Bonferroni's adjustment).

Fig. 4.

Efficacy of E1210 compared to that of voriconazole in a murine model of disseminated candidiasis caused by azole-resistant C. albicans IFM49738. Mice (n = 8) were immunosuppressed with 5-FU administered subcutaneously 6 days prior to infection and then intravenously infected with 5.3 × 10⁴ CFU of Candida albicans. E1210 or voriconazole was administered orally three times daily for three consecutive days starting 1 h after infection. The survival rate and survival period were determined over 14 days. *, P < 0.05 versus control group (log rank test with Bonferroni's adjustment).

Fig. 5.

Effect of treatment delay on the efficacy of E1210 in a murine model of disseminated candidiasis. Mice (n = 8) were immunosuppressed with 5-FU administered subcutaneously 6 days prior to infection and then intravenously infected with 1.4 × 10⁴ CFU of C. albicans IFM49971. E1210 was administered orally three times daily for three consecutive days starting 1 h or 24 h after infection. The survival rate and survival period were determined over 14 days.

Fig. 6.

Efficacies of E1210 and reference antifungals in a murine model of pulmonary aspergillosis caused by A. flavus IFM50915. Mice (n = 9) were immunosuppressed with 5-FU administered subcutaneously 5 days prior to infection and then intranasally infected with 3.0 × 10⁴ of Aspergillus flavus conidia. E1210 or voriconazole was administered orally twice daily and caspofungin or liposomal amphotericin B was administered intraperitoneally once daily for four consecutive days starting 1 h after infection. The survival rate and survival period were determined over 14 days. (A) E1210; (B) voriconazole; (C) caspofungin; (D) liposomal amphotericin B. *, P < 0.05 versus control group (log rank test with Bonferroni's adjustment).

Fig. 7.

Efficacy of E1210 in a murine model of disseminated fusariosis caused by F. solani IFM50956. Mice (n = 8–10) were immunosuppressed with 5-FU administered subcutaneously 6 days prior to infection and then intravenously infected with 5.0 × 10³ of F. solani conidia. E1210 was administered orally three times daily for five consecutive days starting 1 h after infection. The survival rate and survival period were determined over 14 days. *, P < 0.05 versus control group (log rank test with Bonferroni's adjustment).

Fig. 8.

Time-plasma concentration profiles of E1210 after oral and intravenous administrations of a single dose of 1 mg/kg to mice. After administration of E1210, blood samples were drawn from the vena cava of mice at designated time points. After deproteinization with methanol, the extracted sample was analyzed by LC/MS/MS. Each value represents the mean of the results for two animals.