Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in Candida albicans

Weil Tobias and Santamaria Rodrigo and Lee Wanseon and Rung Johan and Tocci Noemi and Abbey Darren and Bezerra Ana R. and Carreto Laura and Moura Gabriela R. and Bayes Monica and Gut Ivo G. and Csikász-Nagy Attila and Cavalieri Duccio and Berman Judith and Santos Manuel A. S.: Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in Candida albicans.
mSPHERE, 2 (4). ISSN 2379-5042 (2017)

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Item Type:

Article

Creators:

Creators	ORCID	MTMT szerző azonosító
Weil Tobias
Santamaria Rodrigo
Lee Wanseon
Rung Johan
Tocci Noemi
Abbey Darren
Bezerra Ana R.
Carreto Laura
Moura Gabriela R.
Bayes Monica
Gut Ivo G.
Csikász-Nagy Attila	0000-0002-2919-5601	10012379
Cavalieri Duccio
Berman Judith	0000-0002-8577-0084
Santos Manuel A. S.

Abstract:

Regulated erroneous protein translation (adaptive mistranslation) increases proteome diversity and produces advantageous phenotypic variability in the human pathogen Candida albicans. It also increases fitness in the presence of fluconazole, but the underlying molecular mechanism is not understood. To address this question, we evolved hypermistranslating and wild-type strains in the absence and presence of fluconazole and compared their fluconazole tolerance and resistance trajectories during evolution. The data show that mistranslation increases tolerance and accelerates the acquisition of resistance to fluconazole. Genome sequencing, array-based comparative genome analysis, and gene expression profiling revealed that during the course of evolution in fluconazole, the range of mutational and gene deregulation differences was distinctively different and broader in the hypermistranslating strain, including multiple chromosome duplications, partial chromosome deletions, and polyploidy. Especially, the increased accumulation of loss-ofheterozygosity events, aneuploidy, translational and cell surface modifications, and differences in drug efflux seem to mediate more rapid drug resistance acquisition under mistranslation. Our observations support a pivotal role for adaptive mistranslation in the evolution of drug resistance in C. albicans.

Journal or Publication Title:

mSPHERE

Date:

2017

Volume:

Number:

ISSN:

2379-5042

Institution:

Pázmány Péter Katolikus Egyetem

Kar:

Információs Technológiai és Bionikai Kar (2013.07.-)