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Dissecação de mecanismos moleculares de resistência a antifúngicos em espécies de Candida não albicans
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Orientador(es)
Resumo(s)
As infeções fúngicas são preocupantes para a saúde pública, nomeadamente do género
Candida, devido ao aumento de estirpes resistentes às terapêuticas convencionais e a estarem
associadas a altas taxas de morbilidade e mortalidade. As espécies não albicans destacam-se pela
emergência persistente de estirpes resistentes, contudo, a sua fisiologia e biologia molecular
pouco estudadas têm impedido a compreensão dos mecanismos moleculares subjacentes a estas
resistências. Neste estudo foram analisados 628 isolados identificados como Candida em
pacientes de unidades de saúde da Grande Lisboa verificando-se elevada prevalência de C.
albicans. Uma percentagem significativa de isolados Candida não albicans foram também
identificados destacando-se C. glabrata e C. parapsilosis. Estes isolados de espécies não albicans
foram analisados quanto à sua suscetibilidade a quatro antifúngicos com relevância na prática
clínica. Foram identificados sete isolados como resistentes, seis C. glabrata a fluconazol e três
(dois C. glabrata e um C. tropicalis) a voriconazol, e três isolados (dois C. parapsilosis e um C.
tropicalis) foram identificados como maiores tolerantes a caspofungina, resultando em ~5 % de
prevalência de resistência. A identificação do isolado de C. tropicalis multirresistente, constituiu
um importante resultado visto a identificação destas estirpes multirresistentes ser, habitualmente
rara e não descrita. O estudo das regiões hotspots do gene CpFKS1 pelos dois isolados de C.
parapsilosis resistentes revelaram apenas a existência do polimorfismo natural P660A no hotspot
1, tendo já sido identificado noutros estudos como responsável pelo aumento da tolerância a
equinocandinas. Dos isolados de C. glabrata que se identificaram como resistentes, apenas
ISTE188 se pode correlacionar o fenótipo de resistência com a codificação de uma nova variante
hiperativa do regulador transcricional CgPdr1. Nos restantes cinco isolados resistentes, os
resultados obtidos não permitiram concluir que estes são mutantes do regulador, havendo
possibilidade destes terem adquirido resistência através de um mecanismo independente de
CgPdr1.
Fungal infections are of concern to public health, particularly the genus Candida, due to the increase in strains resistant to conventional therapies and associated with high morbidity and mortality rates. Non-albicans species stand out for the persistent emergence of resistant strains, however, their poorly studied physiology and molecular biology have hindered the understanding of the molecular mechanisms underlying these resistances. In this study we analyzed 628 isolates identified as Candida from patients in healthcare unD1/D2 in Lisbon area and found a high prevalence of C. albicans. A significant percentage of non-albicans Candida isolates were also identified, especially C. glabrata and C. parapsilosis. These non-albicans isolates were analyzed for their susceptibility to four antifungal drugs of relevance in clinical practice. Seven isolates were identified as resistant, six C. glabrata to fluconazole and three (two C. glabrata and one C. tropicalis) to voriconazole, and three isolates (two C. parapsilosis and one C. tropicalis) were identified as higher tolerant to caspofungin, resulting in ~5 % prevalence of resistance. The identification of the multidrug-resistant C. tropicalis isolate was an important result since identification of these multidrug-resistant strains is usually rare and not described. The study of the hotspot regions of the CpFKS1 gene for the two resistant C. parapsilosis isolates revealed only the existence of the natural polymorphism P660A in hotspot 1, which has already been identified in other studies as responsible for increased tolerance to echinocandins. Of the C. glabrata isolates that were identified as resistant, only ISTE188 could correlate the resistance phenotype with the encoding of a novel overactive variant of the transcriptional regulator CgPdr1. In the remaining five resistant isolates, the results obtained did not allow us to conclude that they are mutants of the regulator, with the possibility that they acquired resistance through a CgPdr1 independent mechanism.
Fungal infections are of concern to public health, particularly the genus Candida, due to the increase in strains resistant to conventional therapies and associated with high morbidity and mortality rates. Non-albicans species stand out for the persistent emergence of resistant strains, however, their poorly studied physiology and molecular biology have hindered the understanding of the molecular mechanisms underlying these resistances. In this study we analyzed 628 isolates identified as Candida from patients in healthcare unD1/D2 in Lisbon area and found a high prevalence of C. albicans. A significant percentage of non-albicans Candida isolates were also identified, especially C. glabrata and C. parapsilosis. These non-albicans isolates were analyzed for their susceptibility to four antifungal drugs of relevance in clinical practice. Seven isolates were identified as resistant, six C. glabrata to fluconazole and three (two C. glabrata and one C. tropicalis) to voriconazole, and three isolates (two C. parapsilosis and one C. tropicalis) were identified as higher tolerant to caspofungin, resulting in ~5 % prevalence of resistance. The identification of the multidrug-resistant C. tropicalis isolate was an important result since identification of these multidrug-resistant strains is usually rare and not described. The study of the hotspot regions of the CpFKS1 gene for the two resistant C. parapsilosis isolates revealed only the existence of the natural polymorphism P660A in hotspot 1, which has already been identified in other studies as responsible for increased tolerance to echinocandins. Of the C. glabrata isolates that were identified as resistant, only ISTE188 could correlate the resistance phenotype with the encoding of a novel overactive variant of the transcriptional regulator CgPdr1. In the remaining five resistant isolates, the results obtained did not allow us to conclude that they are mutants of the regulator, with the possibility that they acquired resistance through a CgPdr1 independent mechanism.
Descrição
Tese de Mestrado, Microbiologia Aplicada, 2022, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Antifúngicos Breakpoints Candida não albicans Mutações Resistência antifúngica Teses de mestrado - 2023