title: Drug induced proteome changes in Candida albicans: comparison of the effect of beta(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.
authors.affiliation: Infectious Disease Group, Aventis Pharma, Romainville, France. jean-michel.bruneau@aventis.com
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bruneau
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.forename: Eric
authors.initials: E
authors.lastname: Tagat
authors.forename: Raymond
authors.initials: R
authors.lastname: Legrand
authors.forename: Françoise
authors.initials: F
authors.lastname: Supatto
authors.forename: Claude
authors.initials: C
authors.lastname: Fudali
authors.forename: Jean-Pierre Le
authors.initials: JP
authors.lastname: Caer
authors.forename: Valérie
authors.initials: V
authors.lastname: Labas
authors.forename: Dominique
authors.initials: D
authors.lastname: Lecaque
authors.forename: John
authors.initials: J
authors.lastname: Hodgson
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D015180:Electrophoresis, Gel, Two-Dimensional; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D007091:Image Processing, Computer-Assisted; D017964:Itraconazole / Q000494:pharmacology; D007700:Kinetics; D013058:Mass Spectrometry; D008565:Membrane Proteins; D008855:Microscopy, Electron, Scanning; D008858:Microscopy, Phase-Contrast; D010456:Peptides, Cyclic / Q000494:pharmacology; D020543:Proteome; D029702:Schizosaccharomyces pombe Proteins; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D020543:Proteome; D029702:Schizosaccharomyces pombe Proteins; D014230:Triazoles; D017964:Itraconazole; D015725:Fluconazole; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D005947:Glucose; C052098:mulundocandin