A Case for Two-Component Signaling Systems As Antifungal Drug Targets

The recent outbreak of fungal meningitis caused by Exserohilum rostratum in patients receiving contaminated steroid injections resulted in 64 deaths, receiving a lot of press and briefly bringing into the public eye the difficulty of treating systemic fungal infections [1]. What is generally less well appreciated, however, is that there are several other, much more common fungal pathogens that pose a serious health threat. Indeed, currently more people die from these fungal diseases worldwide than from tuberculosis or malaria [2]. The fungal pathogens most frequently responsible for human mortality are: Aspergillus fumigatus, Candida spp. (predominantly C. albicans), Cryptococcus neoformans, Pneumocystis carinii, and dimorphic fungi that cause endemic mycoses (Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitides, and Paracoccidioides brasiliensis). Fungal pathogens pose an especially high risk to individuals with compromised immunity, and this population of susceptible hosts is growing [3,4]. There has been a steady increase in the incidence of fungal infections over recent decades, primarily due to the AIDS pandemic, an increase in patients receiving cancer chemotherapy and allogeneic bone marrow transplants, a higher incidence of seriously ill patients in intensive care units, and the aging of the human population [3–8]. Despite the extensive list of fungal pathogens and the increasing frequency of their occurrence, we have at our disposal only a very limited number of antifungal drugs. The past two decades have seen the emergence of two classes of antifungals: those that target ergosterol synthesis (the azoles) and those that target cell wall β-1,3 glucan synthase (echinocandins). Of the azoles, the triazoles have gained importance as alternatives to the more toxic amphotericin B. Triazoles are fungistatic and their continued use has resulted in an increase in triazole resistance among formerly sensitive species and a rising number of disease cases caused by intrinsically azole-resistant non-albicans Candida species [4]. Echinocandins are fungicidal and are the drug of choice for treating most fungal infections, but these drugs are not effective in treating infections caused by C. neoformans, and echinocandin resistance is increasing in some Candida species [9]. Clearly, there is an urgent need to discover new drug targets to meet the challenges posed by fungal infections.