Compromising Hsp90 function may provide strategy to make antifungal drugs more effective in the treatment of candida

Fungal pathogens pose a serious threat to people with compromised immune systems. Chief among the opportunistic fungal pathogens is Candida albicans. Treatment of C. albicans infections remains challenging because there are very few effective drugs and the pathogen has evolved many strategies to survive drug exposure. The echinocandins are the only new class of antifungal drug to reach the clinic in decades and they block biosynthesis of an essential component of the fungal cell wall. We discovered that the molecular chaperone Hsp90, which is required for its client proteins in the cell to fold and function, governs the ability of C. albicans to survive exposure to echinocandins. Compromising Hsp90 function renders the echinocandins more effective at killing C. albicans laboratory strains and clinical isolates. Hsp90 orchestrates the crucial responses to cell wall stress exerted by the echinocandins by enabling the function of its client protein calcineurin, which allows the fungus to survive otherwise lethal conditions. Our results suggest that compromising Hsp90 function provides a powerful and much-needed strategy to render existing antifungal drugs more effective in the treatment of life-threatening fungal infections.

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First Publkished in September 2009

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