Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/72539 |
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. |
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Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida kruseiCandida spantifungals(Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamidesmechanisms of actionreactive oxygen speciesergosteroldimorphic transitionmetabolic viability(Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamidesScience & TechnologySystemic 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.This research was partially supported by national funds through FCT—Foundation for Sci ence and Technology within the scope of UID/Multi/04546/2019, UIDB/04423/2020, UIDB/50006/2020, UID/QUI/00686/2020.Multidisciplinary Digital Publishing InstituteUniversidade do MinhoCerqueira, FátimaMaia, MartaGabriel, CarlaMedeiros, RuiCravo, SaraRibeiro, Ana IsabelDantas, DanielaDias, Alice MariaSaraiva, LucíliaRaimundo, LilianaPinto, Eugénia20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/72539engCerqueira, F.; Maia, M.; Gabriel, C.; Medeiros, R.; Cravo, S.; Ribeiro, A.I.; Dantas, D.; Dias, A.M.; Saraiva, L.; Raimundo, L.; Pinto, E. Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei. Antibiotics 2021, 10, 183. https://doi.org/10.3390/antibiotics100201832079-63822079-638210.3390/antibiotics10020183https://www.mdpi.com/2079-6382/10/2/183info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:40:21Zoai:repositorium.sdum.uminho.pt:1822/72539Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:37:08.428650Repositório 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 |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
title |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
spellingShingle |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei Cerqueira, Fátima 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 (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides Science & Technology |
title_short |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
title_full |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
title_fullStr |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
title_full_unstemmed |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
title_sort |
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
author |
Cerqueira, Fátima |
author_facet |
Cerqueira, Fátima Maia, Marta Gabriel, Carla Medeiros, Rui Cravo, Sara Ribeiro, Ana Isabel Dantas, Daniela Dias, Alice Maria Saraiva, Lucília Raimundo, Liliana Pinto, Eugénia |
author_role |
author |
author2 |
Maia, Marta Gabriel, Carla Medeiros, Rui Cravo, Sara Ribeiro, Ana Isabel Dantas, Daniela Dias, Alice Maria Saraiva, Lucília Raimundo, Liliana Pinto, Eugénia |
author2_role |
author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Cerqueira, Fátima Maia, Marta Gabriel, Carla Medeiros, Rui Cravo, Sara Ribeiro, Ana Isabel Dantas, Daniela Dias, Alice Maria Saraiva, Lucília Raimundo, Liliana Pinto, Eugénia |
dc.subject.por.fl_str_mv |
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 (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides Science & Technology |
topic |
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 (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides Science & Technology |
description |
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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021 2021-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/1822/72539 |
url |
http://hdl.handle.net/1822/72539 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Cerqueira, F.; Maia, M.; Gabriel, C.; Medeiros, R.; Cravo, S.; Ribeiro, A.I.; Dantas, D.; Dias, A.M.; Saraiva, L.; Raimundo, L.; Pinto, E. Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei. Antibiotics 2021, 10, 183. https://doi.org/10.3390/antibiotics10020183 2079-6382 2079-6382 10.3390/antibiotics10020183 https://www.mdpi.com/2079-6382/10/2/183 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
publisher.none.fl_str_mv |
Multidisciplinary Digital Publishing Institute |
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 |
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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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1799132903613923328 |