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Avenues for antifungal drug discovery and development: where to now?

An increasing clinical burden of fungal disease is associated with chronic (e.g. chronic pulmonary aspergillosis), systemic (e.g. candidemia and cryptococcal meningoencephalitis), and recurrent (e.g. vulvovaginal candidiasis) infections. Patient populations, such as those with drug-induced immunosuppression or comorbidities including HIV or stem cell and solid organ transplantation, are at high risk of lifethreatening invasive fungal infections (IFIs) [1]. Additionally, the development of resistance to current antifungal therapies, including the emergence of multi-drug resistant species of Candida auris [2] and the increased incidence of voriconazoleresistant Aspergillus fumigatus isolates [3], underscore the need for new approaches in the management of fungal diseases. Discovery and development of agents that overcome resistance mechanisms is crucial. Common mechanisms responsible for innate and acquired drug resistance include the overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily (MFS) transporters [4]. Additionally, single mutations in genes of drug targets are also responsible for the development of resistance as it happens in the case of triazoles and mutations of lanosterol 14α-demethylase (Erg11p/ CYP51) [5]. Antifungal treatments under evaluation can be grouped into four categories: a. new antifungal classes, b. new agents that belong to an existing class of antifungal agents, c. new indications for established antifungal agents, and d. new antifungal strategies. Table 1 notes some ongoing clinical trials evaluating antifungal agents. The chemical structures of some representative antifungal agents under clinical drug discovery evaluation are presented in Figure 1. This editorial outlines some new antifungal concepts and strategies at different stages of evaluation that may supplement the limited existing options for antifungal therapy.