Amphotericin-resistant Aspergillus terreus isolates exhibit a higher adaption to cellular stress

Ref ID: 19364

Author:

E. Jukic, W. Posch, G. Blum, C. Lass-Florl and D. Wilflingseder

Author address:

Division of Hygiene, Austria

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Objectives The majority of Aspergillus (A.) terreus isolates is intrinsi-
cally resistant to amphotericin B (AmB), the most common used
antifungal drug. In this study we are aiming to understand the resis-
tance mechanisms of A. terreus.
Methods For this, microarray analyses were performed to evaluate
gene expression levels in an A. terreus isolates resistant to Amphoteri-
cinB (AmB) upon sublethal treatment with the compound. The differ-
ences in gene expression levels from the resistant A. terreus (ATR)
isolate were compared to data obtained from an AmB-susceptible A.
terreus (ATS). Up-regulation of genes was verified by relative quantifi-
cation using real-time RT-PCR and tubulin as reference gene as well
as by Western Blot analyses to determine the levels of differentially
regulated proteins. The functionality of up-regulated genes was mea-
sured by ROS production, blocking experiments using antioxidants
and inhibitory reagents.
Results We found that upon sublethal AmB treatment 284 out of
10.000 genes were differentially expressed in ATR compared to an
untreated control, while in ATS only 79 genes showed a differential
expression pattern. The majority of up-regulated genes in ATR were
involved in cell stress adaptation, sugar metabolism and signal trans-
duction. Among the highest up-regulated genes associated with cell
stress adaption or cell wall integrity in AmB-treated ATR but not
ATS were found to be aox, hsp70, hsp90, erg1 and erg3. The increase
in those genes was confirmed by relative quantification. To set the
results into a functional context respecting the resistance mecha-
nisms involved, we performed inhibition assays, ROS measurements
and additionally treated the fungal isolates with antioxidative agents.
Lastly, the signalling mechanisms in ATS and ATR were
investigated.
Conclusion In summary we found that AmB resistance is based on
the oxidative character of this compound and the resistant A. terreus
isolate is able to cope with this challenge due to significantly
increased adaption of the cellular stress machinery.

Abstract Number: o3.1

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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