Core histones govern echinocandin susceptibility in <i>Candida glabrata</i>

Echinocandin antifungals, which impede cell wall synthesis, are often used to treat Candida bloodstream infections. The human opportunistic fungal pathogen <i>Candida</i> (Nakaseomyces) <i>glabrata</i> is increasingly being reported to exhibit co-resistance to echinocandins and ergosterol biosynthesis-inhibitory azole drugs in hospitals worldwide. However, the role of histones, protein-building blocks of the nucleosome, in governing echinocandin resistance in <i>C. glabrata</i> is not understood. Herein, we show that the reduced gene dosage of core histone proteins, but not of the linker histone, leads to echinocandin susceptibility, which is partly due to increased ROS levels. Additionally, our data implicate histone H3 acetylation at lysine-56 in the caspofungin response of <i>C. glabrata</i>. Since the emerging echinocandin resistance is an impediment to successful antifungal therapy, our findings open up a new research avenue of pharmacological targeting of histone proteins that could potentially block echinocandin resistance and attenuate <i>C. glabrata</i> survival in the host.