Drug induced proteome changes in Candida albicans: Comparison of the effect of β(1,3) glucan synthase inhibitors and two triazoles, fluconazole and itraconazole

Abstract

The dimorphic fungus Candida albicans is an opportunistic human pathogen. Candidiasis is usually treated with azole antifungal agents. However clinical treatments may fail due to the appearance of resistance to this class of antifungal agents in Candida. Echinocandin derivatives are an alternative for the treatment of these fungal infections and are active against azole resistant isolates of C. albicans. Azoles inhibit the lanosterol 14 alpha demethylase which is a key enzyme in the synthesis of ergosterol. In contrast, the echinocandin class of antibiotics inhibit noncompetitively beta-(1,3)-D-glucan synthesis in vitro. We have investigated the impact of mulundocandin on the proteome of C. albicans and compared it to those of a mulundocandin derivative, as well as to two azoles of different structure, fluconazole and itraconazole. The changes in gene expression underlying the antifungal responses were analyzed by comparative 2-D PAGE. Dose dependant responses were kinetically studied on C. albicans grown at 25 degrees C (yeast form) in synthetic dextrose medium. This study shows that antifungals with a common mechanism of action lead to comparable effects at the proteome level and that a proteomics approach can be used to distinguish different antifungals, with the promise to become a useful tool to study drugs of unknown mechanism of action.

Decoding Serological Response to Candida Cell Wall Immunome into Novel Diagnostic, Prognostic, and Therapeutic Candidates for Systemic Candidiasis by Proteomic and Bioinformatic Analyses

“…A negative correlation has been found between Bgl2p and wall-associated Eno1p in fluconazoletreated Candida cells (69). Furthermore BGL2 deletion results in an increased chitin deposition into the wall (68) that in turn has been associated with up-regulation of cell surface stressrelated proteins like Eno1p (31,63). Taken together, it is conceivable that high anti-Bgl2p antibody concentrations may neutralize Bgl2p activity and somehow stimulate the Eno1p overexpression in compensatory response, thus driving an amplified production of protective Eno1p-neutralizing antibodies.…”

“…IgG antibody levels appeared to increase the risk of SC by no confounding factors and, through the immune response other than that directed against Pgk1p, Eno1p, Met6p, Gap1p, and Fba1p, stress-induced proteins (61)(62)(63)(64)(65). The correlation observed among circulating levels of antibodies against these stress-related proteins, also noted along the course of SC (36,66), may reflect the stressful environment resulting from the Candida invasive process (64,67).…”

Changes in the Proteome of Candida albicans in Response to Azole, Polyene, and Echinocandin Antifungal Agents

“…Proteomic analysis has also been used to study the adaptive response of C. albicans to fluconazole, itraconazole, and mulundocandin (5,49) and to identify changes in protein abundance in matched sets of azolesusceptible and -resistant clinical isolates of C. albicans (15,20). In the present study, we used the combination of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and matrix-assisted laser desorption ionization-time of flight mass spectroscopy (MALDI-TOF MS) to identify the changes in protein abundance in a wild-type strain of C. albicans after exposure to ketoconazole, amphotericin B, and caspofungin.…”

Yeast Proteome Analysis

“…Drug-induced changes in the C. albicans proteome were followed after application of antifungal agents, namely a β -(1,3)-glucan synthase inhibitor, and of two triazoles. Similar changes in the proteome were monitored for the triazoles, demonstrating that this approach can differentiate between antifungal drugs with contrasting mode of action (Bruneau et al, 2003 ).…”