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Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei

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Resumo: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 (<i>Z</i>)-5-amino-<i>N</i>’-aryl-1-methyl-1<i>H</i>-imidazole-4-carbohydrazonamides (2h, 2k, 2l) that had previously demonstrated strong antifungal activity against <i>Candida krusei</i> and <i>C. albicans</i> 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 <i>C. krusei</i> 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 <i>C. krusei</i> versus <i>C. albicans</i> 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 <i>C. albicans</i> virulence mechanism.
Autores principais:Cerqueira, Fátima
Outros Autores:Maia, Marta; Gabriel, Carla; Medeiros, Rui; Cravo, Sara; Ribeiro, Ana Isabel; Dantas, Daniela; Dias, Alice Maria; Saraiva, Lucília; Raimundo, Liliana; Pinto, Eugénia
Assunto:Candida sp antifungals (Z)-5-amino-N&#8217 -aryl-1-methyl-1H-imidazole-4-carbohydrazonamides mechanisms of action reactive oxygen species ergosterol dimorphic transition metabolic viability (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides
Ano:2021
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso aberto
Instituição associada:Universidade do Minho
Idioma:inglês
Origem:RepositóriUM - Universidade do Minho

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