Mapping antifungal drug resistance in Candida albicans by genomic approaches

• Autor(a) principal: Sousa, Gonçalo Filipe Giesta de
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/33030
• topic: Candida albicans; Candidiasis; Antifungals; Resistance evolution; Genomic variation; Phenotypic variation; Mistranslation; Codon ambiguity

Candida albicans is the leading cause of life-threatening invasive fungal 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). Results showed that high levels of mistranslation accelerate the acquisition of azole resistance, but not polyene resistance. Hypermistranslation caused more rapid and frequent evolution of fluconazole resistance mediated through CNVs affecting the classical drug efflux and ergosterol biosynthesis pathways, while itraconazole resistant isolates showed aneuploidies affecting transport. In the evolution with the polyene Amphotericin B, hypermistranslation seemed to delay acquisition of resistance with genome changes summed up to SNPs and INDELs in filamentation genes.