New Mechanisms of Flucytosine Resistance in C. glabrata Unveiled by a Chemogenomics Analysis in S. cerevisiae

• DOI: 10.1371/journal.pone.0135110
• Publication Date: 2015-08-12T18:18:18Z
• Authors: Catarina Costa; Andreia Ponte; Pedro Pais; Rui Santos; Mafalda Cavalheiro; Takashi Yaguchi; Hiroji Chibana; Miguel Cacho Teix...
• Keywords: Flucytosine; Candida glabrata

5-Flucytosine is currently used as an antifungal drug in combination therapy, but fungal pathogens are rapidly able to develop resistance against this drug, compromising its therapeutic action. The understanding of the underlying mechanisms crucial deal with problem. In work, S. cerevisiae deletion mutant collection was screened for increased flucytosine. Through chemogenomics analysis, 183 genes were found confer agent. Consistent known effect DNA, RNA and protein synthesis, most significant Gene Ontology terms over-represented list 5-flucytosine determinants related DNA repair, metabolism. Additional functional classes include carbohydrate nitrogen—particularly arginine—metabolism, lipid metabolism cell wall remodeling. Based on results obtained a model system, further studies conducted pathogenic yeast Candida glabrata. Arginine supplementation relieve inhibitory exerted by C. Lyticase susceptibility increase within first 30min exposure, suggesting act damaging Upon exponential growth resumption presence 5-flucytosine, exhibited higher lyticase, that remodeling occurs response 5-flucytosine. Additionally, aquaglyceroporin encoding CgFPS1 CgFPS2, from glabrata, identified resistance. CgFPS2 mediate resistance, decreasing accumulation glabrata cells.