Enhancement of ROS Production by Catechin Is a Primary Effect of Increased Azole Efficacy in Nakaseomyces glabratus (Candida glabrata) Cells Lacking the ERG6 Gene

Fungal infections have become an important public health problem. Currently, there are only three available classes of antifungals for the treatment of invasive infections. Two of them, azoles and polyenes, target the synthesis of ergosterol or bind to sterols. A promising strategy to improve current therapies is the use of natural compounds in combinational therapies with the existing antifungals. In this work, we analyzed the changes in the susceptibility of the mutant strain of <i>Nakaseomyces glabratus</i> (<i>Candida glabrata</i>) lacking the <i>ERG6</i> gene (encoding the sterol C-24 methyltransferase in ergosterol biosynthesis) in the presence of catechin and antifungal azoles. The reduced content of ergosterol in the <i>Cgerg6</i>Δ mutant resulted in the increased tolerance of the mutant cells to both azoles and polyenes. The combination of catechin with fluconazole or miconazole led to the growth inhibition of the azole-resistant <i>Cgerg6</i>Δ mutant strain. In the presence of catechin and miconazole, the <i>Cgerg6</i>Δ mutant fails to properly activate the expression of genes encoding the transcription factors <i>Cg</i>Yap1p and <i>Cg</i>Msn4p, as well as the gene expression of <i>CgCTA1</i>, which are involved in oxidative stress response and lead to the intracellular accumulation of ROS. Finally, we show that catechin administration reduces mortality in a <i>Galleria mellonella</i> model infected with <i>C. glabrata</i>. Our work thus supports the use of catechin in combination therapies for fungal infections and shows that the <i>CgERG6</i> gene could be a potential new drug target.