Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closel...

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Autores principales:	Tristan Rossignol, Béla Kocsis, Orsolya Bouquet, Ildikó Kustos, Ferenc Kilár, Adrien Nyul, Péter B Jakus, Kshitij Rajbhandari, László Prókai, Christophe d'Enfert, Tamás Lóránd
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dee9c184112c48a18e93b7affb160e50
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spelling	oai:doaj.org-article:dee9c184112c48a18e93b7affb160e502021-11-18T07:47:25ZAntifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.1932-620310.1371/journal.pone.0062142https://doaj.org/article/dee9c184112c48a18e93b7affb160e502013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23646117/?tool=EBIhttps://doaj.org/toc/1932-6203We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 min to 2-(morpholinomethyl)-1-indanone, a representative FMK with a five-membered saturated ring, revealed a transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently, C. albicans lacking the CAP1 gene was hypersensitive to this FMK, while C. albicans strains overexpressing CAP1 had decreased sensitivity to 2-(morpholinomethyl)-1-indanone. Quantitative structure-activity relationship studies revealed a correlation of antifungal potency and the energy of the lowest unoccupied molecular orbital of FMKs and unsaturated Mannich ketones thereby implicating redox cycling-mediated oxidative stress as a mechanism of action. This conclusion was further supported by the loss of antifungal activity upon conversion of representative FMKs to aminoalcohols that were unable to participate in redox cycles.Tristan RossignolBéla KocsisOrsolya BouquetIldikó KustosFerenc KilárAdrien NyulPéter B JakusKshitij RajbhandariLászló PrókaiChristophe d'EnfertTamás LórándPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e62142 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tristan Rossignol Béla Kocsis Orsolya Bouquet Ildikó Kustos Ferenc Kilár Adrien Nyul Péter B Jakus Kshitij Rajbhandari László Prókai Christophe d'Enfert Tamás Lóránd Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
description	We investigated the antifungal activity of fused Mannich ketone (FMK) congeners and two of their aminoalcohol derivatives. In particular, FMKs with five-membered saturated rings were shown to have minimum inhibitory concentration (MIC90s) ranging from 0.8 to 6 µg/mL toward C. albicans and the closely related C. parapsilosis and C. krusei while having reduced efficacy toward C. glabrata and almost no efficacy against Aspergillus sp. Transcript profiling of C. albicans cells exposed for 30 or 60 min to 2-(morpholinomethyl)-1-indanone, a representative FMK with a five-membered saturated ring, revealed a transcriptional response typical of oxidative stress and similar to that of a C. albicans Cap1 transcriptional activator. Consistently, C. albicans lacking the CAP1 gene was hypersensitive to this FMK, while C. albicans strains overexpressing CAP1 had decreased sensitivity to 2-(morpholinomethyl)-1-indanone. Quantitative structure-activity relationship studies revealed a correlation of antifungal potency and the energy of the lowest unoccupied molecular orbital of FMKs and unsaturated Mannich ketones thereby implicating redox cycling-mediated oxidative stress as a mechanism of action. This conclusion was further supported by the loss of antifungal activity upon conversion of representative FMKs to aminoalcohols that were unable to participate in redox cycles.
format	article
author	Tristan Rossignol Béla Kocsis Orsolya Bouquet Ildikó Kustos Ferenc Kilár Adrien Nyul Péter B Jakus Kshitij Rajbhandari László Prókai Christophe d'Enfert Tamás Lóránd
author_facet	Tristan Rossignol Béla Kocsis Orsolya Bouquet Ildikó Kustos Ferenc Kilár Adrien Nyul Péter B Jakus Kshitij Rajbhandari László Prókai Christophe d'Enfert Tamás Lóránd
author_sort	Tristan Rossignol
title	Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
title_short	Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
title_full	Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
title_fullStr	Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
title_full_unstemmed	Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
title_sort	antifungal activity of fused mannich ketones triggers an oxidative stress response and is cap1-dependent in candida albicans.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/dee9c184112c48a18e93b7affb160e50
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Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.

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