Author:
Teppei Arai (JP)
Abstract:
Background: Invasive aspergillosis is one of fungal infections with the poorest prognosis. Clinically, antifungals belonging to three classes -azoles, polyenes, and echinocandins- are used to treat this disease. The nucleoside analogue 5-fluorocytosine (5-FC) is another class antifungal agent, but is rarely used to treat this disease because of its low in vitro susceptibility to A. fumigatus. The mechanism of resistance of A. fumigatus to 5-FC remains unclear. In this study, we report that mutations in components of the complex involved in mRNA polyadenylation and in factors involved in its retention affect 5-FC susceptibility in A. fumigatus.
Methods: To find novel factors associated with altered susceptibility to 5-FC, we performed comparative genomic analysis of A. fumigatus strains with different susceptibilities to 5-FC (MIC >16 and =8) isolated from a same patient. Antifungal susceptibility testing was performed according to CLSI-M38. To investigate the association between newly discovered genetic variants and altered susceptibility to 5-FC, mutant alleles in clinical isolates were replaced with wild-type alleles by the CRISPR-Cas9 system.
Results: Comparative genomic analysis of the two strains identified mutations in Ysh1, a component of the mRNA cleavage and polyadenylation factor (CPF) complex, and CCT7, a member of protein-folding complex called Chaperonin-Containing TCP-1 (CCT), in the strain with increased susceptibility to 5-FC. Replacing the mutant ysh1 and cct7 with the wild-type genes in the strain reduced susceptibility to 5-FC.
Conclusions: This study identified novel genetic changes that influence 5-FC sensitivity. These results suggest that mutations in Ysh1 and CCT7 caused the altered susceptibility to 5-FC observed in this study.
Abstract Number: 51
Conference Year: 2024
Conference abstracts, posters & presentations
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Title
Author
Year
Number
Poster
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v
Katrin Lapp,
Martin Vödisch,
Olaf Kniemeyer,
Ilse D. Jacobsen,
Thorsten Heinekamp,
Axel A. Brakhage2012
PR6.5
n/a
-
v
S. Seyedmousavi*, R.J.M. Bruggemann, W.J.G. Melchers, J.W. Mouton,
P.E. Verweij2012
NULL
n/a
-
v
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2012
27)
n/a
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v
Henriette Irmer, Sonia Tarazona, Ana Conesa
2012
26)
n/a
-
v
Aitor Garzial, Julio Rodrguez-Romero, Reinhard Fischer, Eduardo A. Espeso and Unai Ugaldel.
2012
25)
n/a
-
v
Eline Majoor, Ad Wiebenga, Jos Houbraken, Robert A. Samson, Ronald P. de Vries
2012
70)
n/a
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v
M. Arentshorst, T.R. Jørgensen, J. Park, A.M. van Welzen, G. Lamers, P.A.
vanKuyk, R.A. Damveld and A.F.J. Ram.2011
42)
n/a
-
v
P. Pacheco*, A. Ventura, T. Branco, C. Carvalho, L. Gonçalves,
C. Ferreira2012
R2733
n/a