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

Détails

ID Serval
serval:BIB_75724F4E5569
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Transcriptional activation of heat shock protein 90 mediated via a proximal promoter region as trigger of caspofungin resistance in Aspergillus fumigatus.
Périodique
Journal of Infectious Diseases
Auteur(s)
Lamoth F., Juvvadi P.R., Gehrke C., Asfaw Y.G., Steinbach W.J.
ISSN
1537-6613 (Electronic)
ISSN-L
0022-1899
Statut éditorial
Publié
Date de publication
2014
Volume
209
Numéro
3
Pages
473-481
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Animals, Antifungal Agents/pharmacology, Antifungal Agents/therapeutic use, Aspergillus fumigatus/drug effects, Aspergillus fumigatus/genetics, Disease Models, Animal, Drug Resistance, Fungal, Echinocandins/pharmacology, Echinocandins/therapeutic use, HSP90 Heat-Shock Proteins/biosynthesis, Male, Mice, Promoter Regions, Genetic, Pulmonary Aspergillosis/drug therapy, Pulmonary Aspergillosis/microbiology, Transcriptional Activation
Pubmed
Web of science
Création de la notice
11/10/2016 17:04
Dernière modification de la notice
03/03/2018 18:23
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