Histone Acetylation Regulator Gcn5 Mediates Drug Resistance and Virulence of Candida glabrata

Candida glabrata is poised to adapt to drug pressure rapidly and acquire antifungal resistance leading to therapeutic failure. Given the limited antifungal armamentarium, there is an unmet need to explore new targets or therapeutic strategies for antifungal treatment. The lysine acetyltransferase Gcn5 has been implicated in the pathogenesis of C. albicans. Yet how Gcn5 functions and impacts antifungal resistance in C. glabrata is unknown. Disrupting GCN5 rendered C. glabrata cells more sensitive to various stressors, partially reverted resistance in drug-resistant mutants, and attenuated the emergence of resistance compared to wild-type cells. RNA sequencing (RNA-seq) analysis revealed transcriptomic changes involving multiple biological processes and different transcriptional responses to antifungal drugs in gcn5Δ cells compared to wild-type cells. GCN5 deletion also resulted in reduced intracellular survival within THP-1 macrophages. In summary, Gcn5 plays a critical role in modulating the virulence of C. glabrata and regulating its response to antifungal pressure and host defense. IMPORTANCE As an important and successful human pathogen, Candida glabrata is known for its swift adaptation and rapid acquisition of resistance to the most commonly used antifungal agents, resulting in therapeutic failure in clinical settings. Here, we describe that the histone acetyltransferase Gcn5 is a key factor in adapting to antifungal pressure and developing resistance in C. glabrata. The results provide new insights into epigenetic control over the drug response in C. glabrata and may be useful for drug target discovery and the development of new therapeutic strategies to combat fungal infections.