The role of mistranslation in the acquisition of antifungal resistance

• Autor(a) principal: Figueiredo, Matilde de Almeida
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/28410
• topic: Candida albicans; Experimental evolution; Mistranslation; Drug resistance

Translation of mRNA by the ribosome is a high-fidelity biological process whose error rates range from 10-3 to 10-4 in eukaryotic cells. Such low error rate generalized the idea that mistranslation is a nuisance to the cell without biological relevance. However, recent studies show that translational errors are regulated and play important roles in adaptation to stress situations. Candida albicans, the most prevalent human fungal pathogen, mistranslates naturally at high level in a dynamic way. Exposure of C. albicans to different growth conditions increases mistranslation levels which results in genomic diversification and increased tolerance to antifungals. In this study, we hypothesized that mistranslation accelerates the acquisition of resistance to fluconazole through genomic alterations. To test this hypothesis, we evolved hypermistranslating and wild-type strains in the absence and presence of fluconazole and compared their resistance trajectories during evolution. Results show that mistranslation increases the frequency of acquisition of fluconazole resistance. Ploidy assessment and genome sequencing revealed that during the course of evolution in fluconazole, the range of genomic diversification was broader in the hypermistranslating strains. Specifically, mutations in efflux, drug target and ergosterol biosynthesis genes seem to speed up the acquisition of antifungal drug resistance in hypermistranslating strains. The present work reveals the pivotal role of mistranslation as a mechanism of adaptation of pathogens to antimicrobials.