E1210, a New Broad-Spectrum Antifungal, Inhibits Glycosylphosphatidylinositol (GPI) Biosynthesis and Effects Candida albicans Cell Characteristics

Ref ID: 15164

Author: N. WATANABE, T. HORII, M. MIYAZAKI, K. HATA

Author address:

Eisai Product Creation Systems, Eisai Co., Ltd, Tsukuba, Japan.

Full conference title:

50th Annual ICAAC

Date: 12 September 2014

Abstract:

Background: We discovered E1210, a new broad-spectrum antifungal with a novel mechanism of action. In this study, we determined the inhibitory activity of E1210 against Candida albicans (Ca), Aspegillus fumigatus (Af), and the human Gwt1ps that catalyze the inositol acylation of GPI early in the GPI biosynthesis pathway. In addition, we evaluated some effects of E1210 on C. albicans cells. Methods: For Gwt1p activity, we detected GlcN-(acyl)PI produced from [14C] UDP-GlcNAc in the membrane fractions of yeasts expressing CaGWT1, AfGWT1, or PIG-W (human GWT1) in place of Saccharomyces cerevisiae GWT1. The Als1p level was measured by ELISA. The germ tube formation and adherence of C. albicans were evaluated by crystal violet staining after 1- and 4-h incubations, respectively, in MOPS-buffered RPMI 1640 medium. For biofilm formation, the amount of exopolymeric materials was measured by safranin staining after 24-h incubation in RPMI 1640 medium supplemented with 10% serum. Results: E1210 inhibited the inositol acylation activity of CaGwt1p and AfGwt1p at IC50s of 0.3 to 0.6 μM, but did not inhibit human Gwt1p activity even at 100 μM. In E1210-treated C. albicans, the Als1p expression on the cell surface of C. albicans was significantly lower compared with that of untreated cells, but the Als1p levels in the crude extract were almost the same. E1210 inhibited germ tube formation, adherence on polystyrene surfaces, and biofilm formation of C. albicans at concentrations above its MIC. Fluconazole inhibited neither germ tube formation nor adherence. Micafungin inhibited germ tube formation, but adversely enhanced the adherence. Conclusion: E1210 inhibited the inositol acylation of fungus-specific GPI, which is catalyzed by Gwt1p, leading to the inhibition of GPI-anchored protein maturation. The compound not only inhibited fungal growth, but also suppressed the expression of some virulence factors of C. albicans.

Abstract Number: F1-841

Conference Year: 2010

Link to conference website: NULL

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