B. Kainzner*, S. Perkhofer , G. Blum, C. Lass-Flörl

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Purpose: Invasive aspergillosis (IA) is a leading cause of mortality among immunocompromised individuals and the frequency of Aspergillus spp. infections has increased in recent years. Aspergillus fumigatus (A. fumigatus) is the most common pathogen involved in IA, but at the Innsbruck Medical University the number of infections due to Aspergillus terreus (A. terreus) are increasing. A. terreus is a particular Amphotericin B (AmB) resistant fungus. This study determined whether the essential molecular chaperones Hsp90 and Hsp70 were responsible for the emergence and maintenance of AmB drug resistance in A. terreus. Methods: Therefore each of two strains, A. terreus and A. fumigatus were investigated in more detail. Susceptibility testing for amphotericin B (AmB) was performed according to E-test-method; A. terreus and A. fumigatus showed MICs > 32 μg/ml and MICs 8804; 1 μg/ml, respectively. Hsp90 was blocked with the inhibitor Geldanamycin (5 and 10 μM) and two inhibitors from the calcineurin pathway, which finally also inhibit Hsp90, Cyclosporin A (10 and 20 μM) and Tacrolimus - FK506 (10 μM). Results: The results indicate that the two A. terreus became highly sensitive to AmB, as MICs decreased to 32 μg/ml. Blocking Hsp 90 and Hsp 70 had no significant influence on susceptibility of A. fumigatus; the AmB-MIC was 8804; 1 μg/ml. According to Disc-diffusion-method, susceptibility testing for A. terreus was also carried out with Nystatin in a concentration range from 0,5 μg up to 8 μg. For Hsp90 the same inhibitors were used in equal concentrations; Geldanamycin (5 μM), Cyclosporin A (20 μM) and Tacrolimus FK506 (10 μM). Nystatin in combination with Hsp90 inhibitors had no influence on susceptibility of A. terreus; MIC was > 8 μg Nystatin. To detect Hsp 90 gene expression, Northern Blot analysis were performed for A. terreus and A. fumigatus with sublethal concentrations of 2 μg/ml AmB and 0,25 μg/ml AmB, respectively. The results indicate an upregulation of Hsp 90 gene in A. terreus but not in A. fumigatus. Conclusions: Taken together, these data provide first direct evidence that Hsp90 may be responsible for the AmB resistance in A. terreus.

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4th Advances Against Aspergillosis
    • AAA 4th (2010)