Changes in Ergosterol Biosynthesis Alter the Response to Cycloheximide, 4-Nitroquinoline-N-Oxide, Weak Organic Acids, and Virulence in Candida glabrata

The <i>ERG6</i> gene encodes the sterol C24-methyltransferase converting zymosterol to fecosterol in the ergosterol biosynthetic pathway. Here, we extend the results of functional analysis of the <i>CgERG6</i> gene, which was previously shown to modulate drug susceptibility in <i>Candida glabrata</i> mutant cells, by demonstrating that its deletion leads to increased susceptibility to cycloheximide, 4-nitroquinoline-N-oxide and weak organic acids, and such effects are associated with attenuated virulence. Together with abrogated efflux of drug substrates by <i>Cg</i>Cdr1p and <i>Cg</i>Pdr12p, the <i>Cgerg6Δ</i> mutation leads to reduced cell surface hydrophobicity and decreased virulence of the mutant cells of <i>C. glabrata</i>. The absence of <i>Cg</i>Erg6p impacts the lipid organization and function of the plasma membrane, resulting in non-specific permeability and abrogation of normal function of membrane-bound proteins accompanied by decreased virulence in <i>Cgerg6Δ</i> cells. <i>Galleria mellonella</i> larvae were used as a non-vertebrate animal host model to determine differences in the virulence potential of <i>C. glabrata</i> strains (parental strain and the <i>Cgerg6Δ</i> deletion mutant). We found that <i>Cgerg6Δ</i> mutant strain attenuated in virulence caused 25-30% survival of larvae compared with parental strain.