Exploiting Fungal Virulence-Regulating Transcription Factors As Novel Antifungal Drug Targets

Systemic and invasive mycoses caused by primary and opportunistic fungal pathogens have been emerging as global problems because of the increase in the number of immunocompromised individuals, due to solid-organ transplants, anti-cancer chemotherapy, and extended human lifespan. A recent report estimated that fungal pathogens, such as Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus, are responsible for more than 1 million deaths annually [1]. Despite this, the availability of antifungal drugs or targets for antifungal drug development are very limited. This is unlike the situation of bacterial pathogens and, to an extent, the eukaryotic parasites (which is serious enough) because the animals share a more recent common ancestor with the fungi than other pathogens. Ergosterol and its biosynthetic enzymes are the most popular antifungal drug targets because of the structural distinguishability of ergosterol from cholesterol in mammalian cell membranes. Polyene macrolides directly bind to ergosterol and generate lethal transmembrane channels that leak essential cellular ions and perturb osmotic balances, which leads to cell death [2]. Azole and allylamine derivatives are inhibitors of the ergosterol biosynthetic pathway that inhibit 14α-demethylase and squalene epoxidase, respectively, eventually leading to the accumulation of toxic precursors of ergosterol in the cell membrane and subsequent impairment of membrane integrity [3]. Another promising antifungal drug target is the fungal cell wall. Echinocandin inhibits β1,3-glucan synthase and impairs cell wall integrity [4]. Nucleotide biosynthesis is also, somewhat unexpectedly, an appropriate antifungal drug target. For example, flucytosine itself does not have antifungal activity; however, after its uptake into cells, it is rapidly converted to 5-fluorouracil, which inhibits DNA and protein synthesis by cytosine deaminase, absent in humans [5]. However, all these antifungal drugs have problems, such as toxicity (e.g., hepatotoxicity and nephrotoxicity), frequent emergence of resistance, and a limited spectrum [2–5]. To overcome these problems, novel antifungal drug targets and drugs need to be discovered and developed.