期刊
JOURNAL OF INFECTIOUS DISEASES
卷 209, 期 3, 页码 473-481出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jit530
关键词
aspergillus; heat shock protein 90; caspofungin; paradoxical effect; virulence; invasive aspergillosis; echinocandin; antifungal resistance
资金
- Swiss National Science Foundation [PASMP3-142746]
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [1R21AI097541 01A1]
- Swiss National Science Foundation (SNF) [PASMP3_142746] Funding Source: Swiss National Science Foundation (SNF)
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据