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

Invasive fungal diseases affect approximately 6.5 million people every year, of which about 2.5 million people die worldwide. This number is expected to rise due to increasing numbers of immunosuppressed people, including the elderly, premature infants, organ transplant recipients, cancer, and HIV/AIDS patients. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have both recently emphasized a critical need for the development of new antifungal therapeutics to address expanding drug resistance among human fungal pathogens. The necessity of new antifungal drugs is also underscored by the fact that mortality due to invasive candidiasis has remained unchanged for several decades. However, the discovery of new drugs acting on antifungal drug targets is complicated because fungi are eukaryotes. This greatly limits the number of feasible fungal-specific drug targets. One class of molecules that fulfills the criterion of fungal specificity is chromatin modification enzymes such as lysine acetyltransferase (KATs). The fungal KATs are structurally less well conserved, and some modifications are only found in fungi, minimizing the risk of toxicity, thus making KATs new promising tools for antifungal therapy. We report here that Gcn5 lysine acetyltransferase mediates antifungal drug resistance and virulence of <i>C. auris</i> and represents an important target for antifungal drug discovery.