Mapping antifungal drug resistance in Candida albicans by genomic approaches
Autor(a) principal: | |
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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 |
Resumo: | 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. |
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Mapping antifungal drug resistance in Candida albicans by genomic approachesCandida albicansCandidiasisAntifungalsResistance evolutionGenomic variationPhenotypic variationMistranslationCodon ambiguityCandida 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.Candida albicans é o principal agente causador de infeções fúngicas invasivas potencialmente fatais vida e com taxas de mortalidade associadas que se aproximam dos 40%, apesar do tratamento. A resistência aos azóis comumente usados está a aumentar e os antifúngicos alternativos, como a anfotericina B ou as equinocandinas, aumentam significativamente o custo da terapia antifúngica. Apesar da relevância económica e clínica da resistência aos antifúngicos, este tópico ainda é pouco estudado. Neste estudo, investigou-se o papel dos erros de tradução do mRNA em proteínas, um mecanismo característico usado por C. albicans para diversificar o seu proteoma, na evolução da resistência a antifúngicos. A sequenciação do genoma completo de isolados submetidos a evolução experimental com polienos e azoís foi usada para compreender os caminhos evolutivos que levam ao aparecimento de resistências em estirpes de C. albicans com elevado erro de tradução do mRNA, denominadas “hypermistranslators”. Os resultados demonstraram que elevados níveis de erro aceleram a aquisição de resistência a azóis, mas não a resistência a polienos. “Hypermistranslation” causou um aumento da frequência de aquisição de resistência ao fluconazol através de CNVs que afetam genes de efluxo, alvos da droga e biossíntese de ergosterol, enquanto no itraconazole as aneuploidias afetaram genes de transporte. Na evolução com o polieno, “hypermistranslation” retardou a aquisição de resistência com as alterações genómicas a resumirem-se a SNPs e INDELs em genes de filamentação.2024-01-11T00:00:00Z2021-12-13T00:00:00Z2021-12-13info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/33030engSousa, Gonçalo Filipe Giesta deinfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-02-22T12:03:32Zoai:ria.ua.pt:10773/33030Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:04:32.426881Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
title |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
spellingShingle |
Mapping antifungal drug resistance in Candida albicans by genomic approaches Sousa, Gonçalo Filipe Giesta de Candida albicans Candidiasis Antifungals Resistance evolution Genomic variation Phenotypic variation Mistranslation Codon ambiguity |
title_short |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
title_full |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
title_fullStr |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
title_full_unstemmed |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
title_sort |
Mapping antifungal drug resistance in Candida albicans by genomic approaches |
author |
Sousa, Gonçalo Filipe Giesta de |
author_facet |
Sousa, Gonçalo Filipe Giesta de |
author_role |
author |
dc.contributor.author.fl_str_mv |
Sousa, Gonçalo Filipe Giesta de |
dc.subject.por.fl_str_mv |
Candida albicans Candidiasis Antifungals Resistance evolution Genomic variation Phenotypic variation Mistranslation Codon ambiguity |
topic |
Candida albicans Candidiasis Antifungals Resistance evolution Genomic variation Phenotypic variation Mistranslation Codon ambiguity |
description |
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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-12-13T00:00:00Z 2021-12-13 2024-01-11T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10773/33030 |
url |
http://hdl.handle.net/10773/33030 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799137700523016192 |