In Vitro Activity of E1210, a Novel Antifungal, against Clinically Important Yeasts and Molds

Abstract

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC 90 of <0.008 to 0.06 g/ml), except for Candida krusei (MICs of 2 to >32 g/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC 90 of 0.13 g/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 g/ml), Scedosporium prolificans (MIC of 0.03 g/ml), and Paecilomyces lilacinus (MICs of 0.06 g/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections.

E1210, a New Broad-Spectrum Antifungal, Suppresses Candida albicans Hyphal Growth through Inhibition of Glycosylphosphatidylinositol Biosynthesis

“…YW3548, a natural product, is thought to inhibit the addition of phosphoethanolamine (EtNP) to the first mannose of GPI, but it inhibits both yeast and mammalian GPI-EtNP transferases, although EtNP modification of the first mannose is not essential for the surface expression of GPI-anchored proteins on mammalian cells (22,58). We have modified the prototype compound BIQ (38,59,63) and developed E1210, which possesses potent antifungal activity (19,34). In this study, E1210 was shown to inhibit C. albicans and A. fumigatus Gwt1ps, which are suggested to be involved in the inositol acylation of GlcN-PI in the GPI biosynthesis pathway (36,63,64), but not human Pig-Wp.…”

“…E1210 was as active against C. albicans in biofilms as micafungin and amphotericin B, which are fungicidal agents against C. albicans. The antifungal activity of E1210 is fungistatic (34), but E1210 may be expected to indirectly kill Candida cells in hosts, since the deficiency of GPI reduced the resistance of C. albicans to macrophages (50).…”

“…In our efforts to improve the efficacy of this prototype-inhibitor BIQ (38,59), we next developed E1210, 3-(3-{4-[(pyridin-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-amine (34). This compound showed potent in vitro antifungal activity against a broad range of pathogenic fungi, including Candida spp., Aspergillus spp., and other molds, such as Fusarium and Scedosporium spp., although its action was fungistatic (34), and subsequently showed high therapeutic efficacy in several representative in vivo models of invasive fungal infections (19).…”

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

“…E1210 is a broad spectrum antifungal agent against different pathogenic fungi, including Candida , Aspergillus , Fusarium , and Scedosporium species (190)(191)(192)(193). Importantly, the compound seems to be fungal specifi c and does not inhibit mammalian GPI inositol acylase PIG-W activity ( 194 ).…”

Role of fungal infection in the modern clinic.

“…В экспериментальных моделях пока-зано, что этот препарат отличается свойством снижать повреждающее действие аспергилл на ткани, которое превосходит по силе воздей-ствия азолы и амфотерицин В in vitro. Кроме того, показана более выраженная активность против Scedosporium spp., включая S. prolificans (этот вид резистентен почти ко всем известным антифунгальным препаратам), по сравнению с позаконазолом и вориконазолом [17,27,28]. Разрабатывается новая улучшенная форма су-спензии итраконазола и позаконазол для при-ема внутрь с более высокой биодоступностью.…”