Autor(es):
Cerqueira, Fátima ; Maia, Marta ; Gabriel, Carla ; Medeiros, R. ; Cravo, Sara ; Ribeiro, Ana Isabel ; Dantas, Daniela ; Dias, Alice Maria ; Saraiva, Lucília ; Raimundo, Liliana ; Pinto, Eugénia
Data: 2021
Identificador Persistente: http://hdl.handle.net/10284/10072
Origem: Repositório Institucional - Universidade Fernando Pessoa
Assunto(s): Candida sp.; Antifungals; (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides; Mechanisms of action; Reactive oxygen species; Ergosterol; Dimorphic transition; Metabolic viability; Candida sp.; Candida sp.; Antifungals; Antifungals; (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides; (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides; Mechanisms of action; Mechanisms of action; Reactive oxygen species; Reactive oxygen species; Ergosterol; Ergosterol; Dimorphic transition; Dimorphic transition; Metabolic viability; Metabolic viability
Descrição
Systemic mycoses are one major cause of morbidity/mortality among immunocompromised/debilitated individuals. Studying the mechanism of action is a strategy to develop safer/potent antifungals, warning resistance emergence. The major goal of this study was to elucidate the mechanism of action of three (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides (2h, 2k, 2l) that had previously demonstrated strong antifungal activity against Candida krusei and C. albicans ATCC strains. Activity was confirmed against clinical isolates, susceptible or resistant to fluconazole by broth microdilution assay. Ergosterol content (HPLC-DAD), mitochondrial dehydrogenase activity (MTT), reactive oxygen species (ROS) generation (flow cytometry), germ tube inhibition and drug interaction were evaluated. None of the compounds inhibited ergosterol synthesis. Ascorbic acid reduced the antifungal effect of compounds and significantly decreased ROS production. The metabolic viability of C. krusei was significantly reduced for values of 2MIC. Compounds 2h and 2k caused a significant increase in ROS production for MIC values while for 2l a significant increase was only observed for concentrations above MIC. ROS production seems to be involved in antifungal activity and the higher activity against C. krusei versus C. albicans may be related to their unequal sensitivity to different ROS. No synergism with fluconazole or amphotericin was observed, but the association of 2h with fluconazole might be valuable due to the significant inhibition of the dimorphic transition, a C. albicans virulence mechanism.
