The Future of Antifungal Drug Therapy: Novel Compounds and Targets

Abstract

Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans. However, the currently available antifungals have many limitations, including poor oral bioavailability, narrow therapeutic indices, and emerging drug resistance resulting from their use, thus making it essential to investigate the development of novel drugs which can overcome these limitations and add to the antifungal armamentarium. Advances have been made in antifungal drug discovery research and development over the past few years as evidenced by the presence of several new compounds currently in various stages of development. In the following minireview, we provide a comprehensive summary of compounds aimed at one or more novel molecular targets. We also briefly describe potential pathways relevant for fungal pathogenesis that can be considered for drug development in the near future.

Keywords: acylhydrazones; antifungal agents; arylamidine; calcineurin; drug therapy; new targets; nikkomycin; olorofilm; sphingolipids; threalose.

FIG 1

Structures of the antifungal agents in development.

FIG 2

New antifungal drugs and targets. Acylhydrazones impair the production of glucosylceramide. T-2307 and ilicicolin H act by inhibiting the mitochondrial respiratory chain complexes. AR-12, olorofilm, and mohangamides target metabolism-related enzymes. Tacrolimus and cyclosporine inhibit the fungal calcineurin (Crz1) pathway. ACS, acetyl-CoA synthetase.