Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>

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 und...

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Autores principales:	Tobias Weil, Rodrigo Santamaría, Wanseon Lee, Johan Rung, Noemi Tocci, Darren Abbey, Ana R. Bezerra, Laura Carreto, Gabriela R. Moura, Mónica Bayés, Ivo G. Gut, Attila Csikasz-Nagy, Duccio Cavalieri, Judith Berman, Manuel A. S. Santos
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Candida albicans fluconazole LOH aneuploidy codon ambiguity drug resistance evolution Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/27634fd55d184dabb3cf213225caa91a
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spelling	oai:doaj.org-article:27634fd55d184dabb3cf213225caa91a2021-11-15T15:22:04ZAdaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>10.1128/mSphere.00167-172379-5042https://doaj.org/article/27634fd55d184dabb3cf213225caa91a2017-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00167-17https://doaj.org/toc/2379-5042ABSTRACT 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-of-heterozygosity 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. IMPORTANCE Infectious diseases caused by drug-resistant fungi are an increasing threat to public health because of the high mortality rates and high costs associated with treatment. Thus, understanding of the molecular mechanisms of drug resistance is of crucial interest for the medical community. Here we investigated the role of regulated protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of fluconazole resistance. Such codon ambiguity is usually considered highly deleterious, yet recent studies found that mistranslation can boost adaptation in stressful environments. Our data reveal that CUG ambiguity diversifies the genome in multiple ways and that the full spectrum of drug resistance mechanisms in C. albicans goes beyond the traditional pathways that either regulate drug efflux or alter the interactions of drugs with their targets. The present work opens new avenues to understand the molecular and genetic basis of microbial drug resistance.Tobias WeilRodrigo SantamaríaWanseon LeeJohan RungNoemi TocciDarren AbbeyAna R. BezerraLaura CarretoGabriela R. MouraMónica BayésIvo G. GutAttila Csikasz-NagyDuccio CavalieriJudith BermanManuel A. S. SantosAmerican Society for MicrobiologyarticleCandida albicansfluconazoleLOHaneuploidycodon ambiguitydrug resistance evolutionMicrobiologyQR1-502ENmSphere, Vol 2, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans fluconazole LOH aneuploidy codon ambiguity drug resistance evolution Microbiology QR1-502
spellingShingle	Candida albicans fluconazole LOH aneuploidy codon ambiguity drug resistance evolution Microbiology QR1-502 Tobias Weil Rodrigo Santamaría Wanseon Lee Johan Rung Noemi Tocci Darren Abbey Ana R. Bezerra Laura Carreto Gabriela R. Moura Mónica Bayés Ivo G. Gut Attila Csikasz-Nagy Duccio Cavalieri Judith Berman Manuel A. S. Santos Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>
description	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-of-heterozygosity 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. IMPORTANCE Infectious diseases caused by drug-resistant fungi are an increasing threat to public health because of the high mortality rates and high costs associated with treatment. Thus, understanding of the molecular mechanisms of drug resistance is of crucial interest for the medical community. Here we investigated the role of regulated protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of fluconazole resistance. Such codon ambiguity is usually considered highly deleterious, yet recent studies found that mistranslation can boost adaptation in stressful environments. Our data reveal that CUG ambiguity diversifies the genome in multiple ways and that the full spectrum of drug resistance mechanisms in C. albicans goes beyond the traditional pathways that either regulate drug efflux or alter the interactions of drugs with their targets. The present work opens new avenues to understand the molecular and genetic basis of microbial drug resistance.
format	article
author	Tobias Weil Rodrigo Santamaría Wanseon Lee Johan Rung Noemi Tocci Darren Abbey Ana R. Bezerra Laura Carreto Gabriela R. Moura Mónica Bayés Ivo G. Gut Attila Csikasz-Nagy Duccio Cavalieri Judith Berman Manuel A. S. Santos
author_facet	Tobias Weil Rodrigo Santamaría Wanseon Lee Johan Rung Noemi Tocci Darren Abbey Ana R. Bezerra Laura Carreto Gabriela R. Moura Mónica Bayés Ivo G. Gut Attila Csikasz-Nagy Duccio Cavalieri Judith Berman Manuel A. S. Santos
author_sort	Tobias Weil
title	Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>
title_short	Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>
title_full	Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>
title_fullStr	Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>
title_full_unstemmed	Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>
title_sort	adaptive mistranslation accelerates the evolution of fluconazole resistance and induces major genomic and gene expression alterations in <named-content content-type="genus-species">candida albicans</named-content>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/27634fd55d184dabb3cf213225caa91a
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Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in <named-content content-type="genus-species">Candida albicans</named-content>

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