The Gcn5 lysine acetyltransferase mediates cell wall remodeling, antifungal drug resistance, and virulence of Candida auris

Candida auris has emerged as a multidrug-resistant human fungal pathogen that causes infections of high morbidity and mortality. However, the molecular mechanisms underlying pronounced multidrug resistance and host-pathogen interactions are poorly understood. Here, we show that C. auris GCN5 lysine acetyltransferase is essential for cell wall remodeling, antifungal drug resistance, and virulence. The Candida albicans GCN5 has previously been shown to be an important regulator of antifungal drug resistance and virulence. Therefore, to identify Gcn5-dependent evolutionary conserved as well as divergent transcriptional networks between the two species, we performed comparative transcriptional analysis. The gene set enrichment analysis of C. auris vs C. albicans gcn5 Delta transcriptomic data revealed several major biological pathways and processes including sphingolipid metabolism and glycosylphosphatidylinositol anchor biosynthesis to be enriched in both species. Consistent with these data, we found a prominent role for C. auris Gcn5 in maintaining cell-wall architecture, as the C. auris gcn5 Delta mutant demonstrated a significant increase in cell-surface beta-glucan exposure and chitin content. Additionally, we observed that Gcn5 modulates susceptibility to caspofungin and was required for fungal survival when challenged with primary murine macrophages and neutrophils ex vivo. Furthermore, disruption of GCN5 causes virulence attenuation in a murine model of disseminated candidiasis. Lastly, lysine acetyltransferase inhibitor cyclopentanone, 2-[4-(4-chlorophenyl)-2-thiazolyl] hydrazone displayed antifungal activity either alone or in combination with caspofungin against the drug-resistant C. auris wild-type strain. Collectively, these data provide new insights into the mechanisms of antifungal drug resistance and C. auris-host interactions and suggest Gcn5 lysine acetyltransferase as a potential target for antifungal therapy.