Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs?

According to the World Health Organization, infectious diseases stand out as the major cause of death worldwide. Although bacterial, viral, and parasitic infections appear to constitute the major threat, the clinical relevance of fungal infections has not been adequately recognized. In fact, invasive fungal infections constitute a biomedical problem of epic proportions, because a handful of human fungal pathogens claim an estimated 1.5 million lives per year [1]. Importantly, invasive fungal diseases represent leading causes of morbidity and mortality in immunocompromised individuals, particularly in patients with hematological malignancies, bonemarrow and organ transplant recipients, intensive care unit patients, preterm neonates, and patients with inborn or acquired immune deficiencies such as AIDS [2]. The vast majority of fungal infections are caused primarily by Candida albicans, Aspergillus fumigatus, and Cryptococcus spp. [2]. The overall mortality rate of 35%–40% for candidemia alone exceeds all gram-negative acute bacterial septicemia [3]. Importantly, pronounced inherent clinical antifungal drug resistance, especially in species like Candida glabrata [4], promotes a dramatic increase of infections [5, 6]. The unsolved challenge of getting fast, reliable, and accurate pathogen-specific clinical diagnosis of fungi has remained as another major impediment to successful and efficient antifungal therapy [7]. A mere four chemical entities (polyenes, azoles, echinocandins, and flucytosine) constitute the armory of clinically relevant drugs [1]. A few variant azoles and echinocandins received recent United States Food and Drug Administration (FDA) approval, but new chemical entities are either missing or mainly experimental in nature [8]. Of note, vaccination against fungal infections is currently unavailable and heavily debated, although recent clinical trials may hold new promises as well as challenges ahead [9–11]. Interestingly enough, compelling evidence indicates that chromatin tightly controls fungal virulence and/or pathogen fitness in the host. Nucleosome remodeling and assembly pathways impact the dynamic interplay with host immune surveillance, facilitate immune evasion, as well as drive antifungal drug resistance [12]. For example, several lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) control fungal virulence [13]. This suggests that KATs/KDACs modifying both histones and non-histone targets could aid in antifungal drug discovery [13, 14]. Here, we provide a comprehensive overview of chromatin modifications in human fungal pathogens, particularly those altering virulence (Table 1, Fig 1). However, owing to space constraints, we will focus our discussion on KDACs/KATs in Candida spp. In addition, we discuss how the modulation of KATs/KDACs in Candida spp. could pave the way for novel therapeutic strategies to combat fungal infections [13].