Antifungal Drug Discovery: Something Old and Something New

Invasive fungal infections are devastating. Despite state-of-theart antifungal therapy, the mortality rates for invasive infections with the three most common species of human fungal pathogens are Candida albicans, 20%–40% [1]; Aspergillus fumigatus, 50%–90% [1]; and Cryptococcus neoformans, 20%–70% [2]. Although invasive fungal infections can affect people with intact immune systems, the vast majority of disease occurs in the setting of an immunocompromised host. As discussed recently, the dismal outcomes for invasive fungal infections cannot be completely attributed to a lack of efficacious antifungal drugs [3]. However, because most patients with invasive fungal infections are immunocompromised, the immune system cannot effectively assist in the clearance of the infection, and consequently, the success of treatment is more dependent on the efficacy of the antifungal agent than in the setting of an immunocompetent host. Unfortunately, our repertoire of antifungal agents is limited, particularly in comparison to the number of agents available for bacterial infections. In fact, it took 30 years for the newest class of antifungal drugs, the echinocandins, to progress from bench-to-beside (Figure 1A). Furthermore, it is sobering to consider that the gold standard therapy for cryptococcal meningitis, a disease that kills more than 650,000 per year world-wide [2], is based on medications (amphotericin B and flucytosine) that were discovered nearly 50 years ago.