Transcriptional Activation of Heat Shock Protein 90 Mediated Via a Proximal Promoter Region as Trigger of Caspofungin Resistance in Aspergillus fumigatus

• Published in: The Journal of infectious diseases Vol. 209; no. 3; pp. 473 - 481
• Main Authors: Lamoth, Frédéric, Juvvadi, Praveen R., Gehrke, Christopher, Asfaw, Yohannes G., Steinbach, William J.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-02-2014
• Subjects: Animals; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Antifungals; Aspergillosis; Aspergillus fumigatus; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - genetics; Biological and medical sciences; Disease Models, Animal; Drug Resistance, Fungal; Echinocandins - pharmacology; Echinocandins - therapeutic use; Fundamental and applied biological sciences. Psychology; Fungal infections; FUNGI; Gene expression; Heat shock proteins; HSP90 Heat-Shock Proteins - biosynthesis; Infectious diseases; Lipopeptides; Major and Brief Reports; Male; Medical sciences; Mice; Microbiology; Miscellaneous; Mycology; Polymerase chain reaction; Promoter regions; Promoter Regions, Genetic; Pulmonary Aspergillosis - drug therapy; Pulmonary Aspergillosis - microbiology; Pulmonary Aspergillosis - pathology; Repression; Transcriptional Activation; paradoxical effect; invasive aspergillosis; virulence; echinocandin; aspergillus; caspofungin; heat shock protein 90; antifungal resistance; Fungi; Infection; Resistance; Antifungal agent; Caspofungin; Heat shock protein; Fungi Imperfecti; Aspergillus fumigatus; Echinocandine derivatives
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jit530

Invasive aspergillosis is a deadly infection for which new antifungal therapies are needed. Heat shock protein 90 (Hsp90) is an essential chaperone in Aspergillus fumigatus representing an attractive antifungal target. Using a thiamine-repressible promoter (pthiA), we showed that genetic repression of Hsp90 significantly reduced virulence in a murine model of invasive aspergillosis. Moreover, substituting the A. fumigatus hsp90 promoter with 2 artificial promoters (potef, pthiA) and the Candida albicans hsp90 promoter resulted in hypersensitivity to caspofungin and abolition of the paradoxical effect (resistance at high caspofungin concentrations). By inducing truncations in the hsp90 promoter, we identified a 100-base pair proximal sequence that triggers a significant increase of hsp90 expression (≥1.5-fold) and is essential for the paradoxical effect. Preventing this increase of hsp90 expression was sufficient to abolish the paradoxical effect and therefore optimize the antifungal activity of caspofungin.