In Vitro Activity of E1210 and In Vivo Activity of E1211: A Water-Soluble Prodrug of E1210 in Combination with Other Antifungals

Ref ID: 18655

Author:

N. Watanabe, PhD (Doctor of Philosophy) – Senior Principal Scientist, T. Horii – Scientist, M. Miyazaki – Senior Scientist, K. Hata – Principal Scientist;

Author address:

Eisai Co., Ltd, Tsukuba, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: E1210 is a new broad-spectrum antifungal that inhibits the biosynthesis of fungal glycosylphosphatidylinositol (GPI). E1210 shows potent inhibitory effects on fungal cell growth since GPI-anchored proteins are important components of fungal cell walls. In this study, we examined in vitro activity of E1210 and in vivo activity of E1211, a water-soluble prodrug of E1210, in combination with other antifungals. Methods: The in vitro combination effects of E1210 plus other antifungals [fluconazole (FLCZ), voriconazole (VRCZ), micafungin (MCFG), caspofungin (CSFG), and amphotericin B (AMPH)] were assessed against Candida spp. and Aspergillus spp. using a checkerboard method. MICs were determined using a broth microdilution method. Fractional inhibitory concentration indices (FICIs) were calculated. The in vivo combination effects of E1211 plus MCFG or CSFG were assessed in a murine model of pulmonary aspergillosis. Results: E1210 plus FLCZ, VRCZ, or AMPH demonstrated in vitro synergistic activity against some strains of Candida spp. and E1210 plus MCFG or CSFG showed in vitro synergistic activity against most strains of Aspergillus spp. No antagonism was observed for the combination of E1210 and any antifungal tested. In the murine model of Aspergillus flavus pulmonary aspergillosis, the efficacy of E1211 was enhanced in the presence of MCFG or CSFG. Conclusions: These results suggest the potential clinical usefulness of E1210 and E1211, as the first-in-class antifungal drug. E1210 and E1211 demonstrated synergy in combination with other antifungals in vitro and in vivo against major pathogenic fungi such as Candida spp. and Aspergillus spp.

Abstract Number: F1-1378

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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