Adaptive mistranslation accelerates the evolution of fluconazole resistance and induces major genomic and gene expression alterations in Candida albicans

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere00167-17
JournalmSphere
Volume2
Issue number4
DOIs
StatePublished - 1 Jul 2017

Keywords

  • Aneuploidy
  • Candida albicans
  • Codon ambiguity
  • Drug resistance evolution
  • Fluconazole
  • LOH
  • Phenotypic variability
  • Protein mistranslation

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