Unravelling the role of mistranslation in the acquisition of drug tolerance and resistance in Candida albicans.

Candida albicans is the leading cause of life-threatening invasive infections with mortality rates approaching 40%, despite treatment. Resistance to the commonly used azoles is increasing and alternative antifungals, such as amphotericin B or echinocandins, increase the cost of antifungal therapy. Despite the economic and clinical relevance of antifungal drug resistance, this subject remains poorly studied. Here, we investigated the role of protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of antifungal resistance. We used whole-genome sequencing to unravel the evolutionary paths leading to the emergence of resistance in hypermistranslating C. albicans strains subjected to experimental evolution with drugs from two major classes of antifungals (polyenes, azoles). This experiment resulted in the selection of resistant hypermistranslating isolates exhibiting distinct levels of resistance and different mutation patterns.