Publicação
Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei
| 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’ -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 |
| _version_ | 1866877574624313344 |
|---|---|
| author | Cerqueira, Fátima |
| 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 |
| 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 |
| contributor_name_str_mv | Universidade do Minho |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Cerqueira, Fátima\"},{\"Person.name\":\"Maia, Marta\"},{\"Person.name\":\"Gabriel, Carla\"},{\"Person.name\":\"Medeiros, Rui\"},{\"Person.name\":\"Cravo, Sara\"},{\"Person.name\":\"Ribeiro, Ana Isabel\"},{\"Person.name\":\"Dantas, Daniela\"},{\"Person.name\":\"Dias, Alice Maria\"},{\"Person.name\":\"Saraiva, Lucília\"},{\"Person.name\":\"Raimundo, Liliana\"},{\"Person.name\":\"Pinto, Eugénia\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Universidade do Minho |
| datacite.creators.creator.creatorName.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 |
| datacite.date.Accepted.fl_str_mv | 2021-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-05-06T13:10:01Z |
| datacite.date.embargoed.fl_str_mv | 2021-05-06T13:10:01Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.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 |
| datacite.titles.title.fl_str_mv | Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
| dc.contributor.none.fl_str_mv | Universidade do Minho |
| dc.creator.none.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.date.Accepted.fl_str_mv | 2021-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-05-06T13:10:01Z |
| dc.date.embargoed.fl_str_mv | 2021-05-06T13:10:01Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | https://hdl.handle.net/1822/72539 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | Multidisciplinary Digital Publishing Institute |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.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 |
| dc.title.fl_str_mv | Mechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida krusei |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| 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. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://prod-dspace.uminho.pt/bitstreams/46ca6e24-7491-4f63-8724-d2be8093ddf8/download |
| id | rum_ab45e95b6ccdfd332697cad1ddb96dfd |
| identifier.url.fl_str_mv | https://hdl.handle.net/1822/72539 |
| instacron_str | repositorium |
| institution | Universidade do Minho |
| instname_str | Universidade do Minho |
| language | eng |
| network_acronym_str | rum |
| network_name_str | RepositóriUM - Universidade do Minho |
| oai_identifier_str | oai:repositorium.uminho.pt:1822/72539 |
| organization_str_mv | urn:organizationAcronym:repositorium |
| person_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 |
| publishDate | 2021 |
| publisher.none.fl_str_mv | Multidisciplinary Digital Publishing Institute |
| reponame_str | RepositóriUM - Universidade do Minho |
| repository_id_str | urn:repositoryAcronym:rum |
| service_str_mv | urn:repositoryAcronym:rum |
| spelling | engMultidisciplinary Digital Publishing InstituteSystemic 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.application/pdfMechanism of Antifungal Activity by 5-Aminoimidazole-4-Carbohydrazonamide Derivatives against Candida albicans and Candida kruseiCerqueira, FátimaMaia, MartaGabriel, CarlaMedeiros, RuiCravo, SaraRibeiro, Ana IsabelDantas, DanielaDias, Alice MariaSaraiva, LucíliaRaimundo, LilianaPinto, EugéniaHostingInstitutionOrganizationalUniversidade do Minhoe-mailmailto:repositorium@usdb.uminho.ptrepositorium@usdb.uminho.ptISSNIsPartOf2079-6382DOIIsPartOf10.3390/antibiotics100201832021-05-06T13:10:01Z20212021-03-12T14:38:20Z2021-01-01T00:00:00ZHandlehttps://hdl.handle.net/1822/72539http://purl.org/coar/access_right/c_abf2open accessCandida 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-carbohydrazonamides1154357 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://prod-dspace.uminho.pt/bitstreams/46ca6e24-7491-4f63-8724-d2be8093ddf8/download |
| 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 |
| status | SINGLETON |
| subject.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 |
| title | 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_short | 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 |
| 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 |
| topic_facet | 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 |
| url | https://hdl.handle.net/1822/72539 |
| visible | 1 |