The pathogenic fungus Candida glabrata is the second most common causative agent of candidiasis, and systemic infections have been linked to the death of immunocompromised selleck chemical and immunosuppressed patients (Fidel et al., 1999; Pfaller & Diekema, 2007). Sequencing studies have revealed that C. glabrata is more closely related to Saccharomyces cerevisiae than to Candida albicans (Barns et al., 1991), with some genes functionally interchangeable between C. glabrata and S. cerevisiae (Kitada et al., 1995). Many C. glabrata strains,

relative to S. cerevisiae or C. albicans, have reduced susceptibility to azole antifungals, which inhibit the C-14 demethylase enzyme required for ergosterol synthesis. Recent studies have revealed that the in vitro addition of serum or bile results in enhanced growth of C. glabrata strains that have become auxotrophic for ergosterol due to previous treatment with azole antifungals. These sterol auxotrophs accumulate squalene or squalene oxides and grow when supplemented with cholesterol, serum or bile additives (Nakayama et al., 2000; Bard et al., 2005). Furthermore, addition of serum was also suggested to lower azole susceptibility of

clinical isolates selleck screening library of C. albicans (Nagi et al., 2009). Thus, serum can ameliorate the effects of sterol biosynthetic inhibitors if Candida becomes competent to take up serum cholesterol (Nakayama & Arisawa, 2003). In yeast, FPP synthase encoded by ERG20 catalyzes the sequential 10-4 condensation of two molecules of isoprenyl pyrophosphate, with dimethylallyl pyrophosphate initially resulting in Dolutegravir solubility dmso the 10-carbon compound geranyl pyrophosphate (GPP), which in turn can be further elongated to produce the 15-carbon compound FPP. Therefore, changes in Erg20p activity may likely alter the flux of isoprenoid intermediates

through these various pathways and thus play a central role in the regulation of a number of essential functions in cells. Statins, which inhibit HMG-CoA reductase (Fig. 1), have been demonstrated to cause growth defects in the pathogenic fungi, C. glabrata, C. albicans and Aspergillus fumigatus (Macreadie et al., 2006). Thus, inhibitors of Erg20p might have potent antifungal activities because Erg20p dysfunction would not only affect sterol synthesis but also other cellular process such as protein prenylation. Protein prenylation derived from FPP derivatives is required for the proper localization and function of membrane-associated proteins that participate in a variety of cellular functions, such as the control of cell growth, differentiation, cytokinesis, membrane trafficking and signal transduction (Schafer et al., 1989).