Fungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

Since the 1950s, antifungal drug discovery has identified three classes of natural products (griseofulvin, polyenes and echinocandins) and four classes of synthetic chemicals (allylamines, azoles, flucytosine and phenylmorpholines) with clinical value against fungal infections. For life threatening fungal disease, the polyene amphotericin B is still a common choice despite toxic side-effects. The azoles remain the most widely used group of anti fungals active against a wide range of mycoses, benefiting from creative chemistry to boost their effectiveness. More recently, the echinocandins show great promise, with caspofungin licensed for clinical use in 2002 and two other molecules close to registration. New advances in molecular genetics afford the promise of revealing new antifungal targets, together with new agents to inhibit those targets specifically.

Fungal pathogens are using several mechanisms to circumvent the inhibitory actions of antifungal drugs. The variety of these mechanisms was revealed in recent years by several laboratories with molecular approaches. Besides the identification of genes involved in antifungal drug resistance and the discovery of alternative pathways of resistance (i.e. biofilm formation), novel concepts in the understanding of the survival of fungal pathogen in the presence of antifungal drug (antifungal tolerance) have emerged.