The fungal Achilles' heel: targeting Hsp90 to cripple fungal pathogens.

There is a pressing need for new therapeutic strategies for life-threatening fungal infections. Targeting the molecular chaperone Hsp90 has emerged as a promising approach to cripple fungal pathogens, thereby enhancing antifungal efficacy, impairing the evolution of drug resistance, and rendering resistant pathogens responsive to treatment. Hsp90 inhibitors in clinical development for cancer may be repurposed for some therapeutic applications, though others require fungal selective Hsp90 inhibitors or alternative strategies to inhibit the chaperone machinery. Novel targets include upstream regulators of Hsp90 function and downstream effectors, such as co-chaperones, lysine deacetylases, kinases, and phosphatases. As a hub of cellular circuitry governing stress responses, drug resistance, morphogenesis, and virulence, Hsp90 serves as a fungal Achilles' heel, with broad therapeutic potential.