LAUSR

The global impact of fungal infections on human health has recently been highlighted by several important publications, and advocacy groups. Although several factors undoubtedly contribute to the estimated 1.5 million deaths due to fungal disease each year, the relative paucity of antifungal drugs is likely to play a significant role. The goal of this special issue of Virulence is to highlight recent developments in the effort to address this unmet clinical need. Since the dawn of the age of anti-infective drugs early last century, only 3 classes of antifungal drugs have been developed for the treatment of life-threatening, invasive fungal infections: polyenes (e.g., amphotericin B); azoles (e.g., fluconazole), and echinocandins (e.g., micafungin). As a comparison, 5 distinct classes of drugs are currently used to treat HIV and 2 of these agents have been developed since the introduction of the most recently introduced antifungal class, the echinocandins. Amphotericin B was developed in the late 1950s and remains part of the treatment of choice for the treatment of cryptococcal meningitis, the fungal infection that kills more people on this planet than any other. Additionally, it remains the only treatment option for some types of mold infections that are emerging in severely immunocompromised patients. Consequently, the state-of-theart therapy for some of the most severe fungal diseases faced by our patients has not changed in over 50 y. This is not to say that the field has been entirely static. Most importantly, on-going efforts toward extending the spectrum of azole antifungals to include non-Aspergillus molds represent clinically significant progress; these and other developments within the existing classes of antifungal drugs are discussed by Chen and co-authors. Despite these improvements, the need for truly novel agents is undeniable. Indeed, the development of novel chemical and mechanistic classes of anti-infective agents is a critical goal for nearly every area of infectious diseases. The need, however, is especially acute for the field of antifungals given the small number of available classes. The urgency of this endeavor is underscored by the recent emergence of multi-drug resistant C. glabrata and C. auris. In the example of C. glabrata, patients who are infected with azoleand echinocandin-resistant isolates must be treated with amphotericin B-based regimens and, as discussed above, are essentially being treated as if they contracted their infection in 1962. Given the slow pace of novel antifungal drug development (30 y elapsed between the discovery of the echinocandins and their introduction into clinical practice), the combination of adjuvant agents with currently used drugs to overcome resistance must be consider an important option to addressing this problem. Precedence for this strategy comes from the addition of b-lactamase inhibitors to b-lactams to block resistance in bacteria. In separate contributions, Wright and Rogers discuss progress in approaches to the rationale development of effective antifungal combinations. In addition, Chen discusses the efforts to exploit synergistic interactions between currently used antifungals as part of their broader discussion of new developments associated with established antifungal drugs. Although combination therapy has been widely applied to other areas of infectious disease, including HIV, TB and malaria treatment, such approaches would ideally also involve the development of agents with novel mechanisms of action. In this issue, Perfect, Steinbach, and Li discuss developments toward exploiting trehalose, calcineurin, and the mitochondria as the target of novel small molecules with antifungal activity. If ever there was a time for “outside-the-box (OSTB)” thinking, it has arrived for the discovery of novel antifungal agents and these researchers are venturing into box-free zones to find new treatments. One of the most vexing problems of traditional approaches to antifungal drug discovery is that they frequently lead to the repetitive re-discovery of the same chemical matter or slightly different