| Summary: | Invasive infections caused by the opportunistic pathogen <i>Candida glabrata</i> are treated with echinocandin antifungals that target β-1,3-glucan synthase, an enzyme critical for fungal cell wall biosynthesis. Echinocandin resistance develops upon mutation of genes (<i>FKS1</i> or <i>FKS2</i>) that encode the glucan synthase catalytic subunits. We have analyzed cellular factors that influence echinocandin susceptibility and here describe effects of the post-transcriptional regulator Ssd1, which in <i>S. cerevisiae</i>, can bind cell wall related gene transcripts. The <i>SSD1</i> homolog in <i>C. glabrata</i> was disrupted in isogenic wild type and equivalent <i>FKS1</i> and <i>FKS2</i> mutant strains that demonstrate echinocandin resistance (MICs ˃ 0.5 µg/mL). A reversal of resistance (8- to 128-fold decrease in MICs) was observed in <i>FKS1</i> mutants, but not in <i>FKS2</i> mutants, following <i>SSD1</i> deletion. Additionally, this phenotype was complemented upon expression of <i>SSD1</i> from plasmid (p<i>SSD1</i>). All <i>SSD1</i> disruptants displayed susceptibility to the calcineurin inhibitor FK506, similar to <i>fks1</i>∆. Decreases in relative gene expression ratios of <i>FKS1</i> to <i>FKS2</i> (2.6- to 4.5-fold) and in protein ratios of Fks1 to Fks2 (2.7- and 8.4-fold) were observed in <i>FKS</i> mutants upon <i>SSD1</i> disruption. Additionally, a complementary increase in protein ratio was observed in the p<i>SSD1</i> expressing strain. Overall, we describe a cellular factor that influences Fks1-specific mediated resistance and demonstrates further differential regulation of <i>FKS1</i> and <i>FKS2</i> in<i> C. glabrata</i>.
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