Transcriptional activation of heat shock protein 90 mediated via a proximal promoter region as trigger of caspofungin resistance in Aspergillus fumigatus.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lamoth, F; Juvvadi, PR; Gehrke, C; Asfaw, YG; Steinbach, WJ

Published Date

  • February 2014

Published In

Volume / Issue

  • 209 / 3

Start / End Page

  • 473 - 481

PubMed ID

  • 24096332

Pubmed Central ID

  • 24096332

Electronic International Standard Serial Number (EISSN)

  • 1537-6613

International Standard Serial Number (ISSN)

  • 0022-1899

Digital Object Identifier (DOI)

  • 10.1093/infdis/jit530

Language

  • eng