Fitness of A. fumigatus Cyp 51A triazole resistant strains

Ref ID: 19492

Author:

I Valsecchi1*, R Beau1, JP Latgé1

Author address:

1Aspergillus Unit, Pasteur Institute, Paris, France

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
The emergence of A. fumigatus triazole resistant strains makes the antifungal triazole treatment
obsolete for patients colonized by resistant strains. There are three known triazole resistance
mechanisms in A. fumigatus: Cyp51A aminoacid substitutions due to point mutations; Cyp51A
overexpression due to a tandem repeats in their promoter, and overexpression of efflux pumps that
expel azoles consuming energy or exchanging H+. In order to understand the low environmental
dispersion of some of the A. fumigatus triazole resistant strains, we decided to analyze the fitness
in vivo and in vitro of A. fumigatus strains carrying the mutations M220K or G54W.
Methods:
M220K or G54W Cyp51A mutants were constructed with a barcode of 40 specific nucleotides long,
which allowed us to design primers in order to difference and quantify them by qPCR. To restore the
wild type (wt) phenotype, complemented M220K and G54W Cyp51A strains were also constructed.
Sequencing and testing for itraconazole sensitivity were carried out for all strains.
Results:
M220K or G54W Cyp51A mutants became itraconazole resistant with a MIC ≥ 30 μg/ml after
transformation. No significant differences in ct values between wt and mutant strains were found, in
vitro or in lungs of immune-suppressed mice. The complemented strains restored the phenotype as
wt, MICs (8804; 0.25 μg/ml),
Conclusion:
Wt and mutants strains grew comparably in vitro and in vivo assays. Reversion to wt suggested that
the triazole resistance was due to only the presence of these point mutations.

Abstract Number: 20

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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