Transcriptional Activation of Heat-Shock Protein 90 (Hsp90) Mediated Via a Proximal Promoter Region Confers Caspofungin Resistance in Aspergillus fumigatus.
J Infect Dis. 2013 Oct 4;
Authors: Lamoth F, Juvvadi PR, Gehrke C, Asfaw YG, Steinbach WJ
Invasive aspergillosis is a deadly infection for which new antifungal therapies are needed. The 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 two 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-bp 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.
PMID: 24096332 [PubMed - as supplied by publisher]