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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.

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