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Progress and prospects for targeting Hsp90 to treat fungal infections

Published online by Cambridge University Press:  20 February 2014

AMANDA VERI  and
LEAH E. COWEN
AMANDA VERI
Affiliation:
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
LEAH E. COWEN*
Affiliation:
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
*
*Corresponding author: Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 4368, Toronto, Ontario M5S 1A8, Canada. E-mail: leah.cowen@utoronto.ca
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Summary

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.

Keywords

Hsp90fungal pathogenCandidaAspergillusantifungal drug resistanceantifungal agentazolesechinocandinscombination therapy
Type
Special Issue Article
Information
Parasitology , Volume 141 , Special Issue 9: Heat shock proteins as drug targets in infectious diseases , August 2014 , pp. 1127 - 1137
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Copyright
Copyright © Cambridge University Press 2014 

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