Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans

Tristan Rossignol, Béla Kocsis, Orsolya Bouquet, Ildikó Kustos, F. Kilár, Adrien Nyul, Péter B. Jakus, Kshitij Rajbhandari, László Prókai, Christophe d'Enfert, T. Lóránd

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere62142
JournalPLoS One
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 30 2013

Fingerprint

Oxidative stress
Candida
ketones
Ketones
Candida albicans
stress response
Oxidative Stress
oxidative stress
Oxidation-Reduction
Aspergillus
quantitative structure-activity relationships
Molecular orbitals
Quantitative Structure-Activity Relationship
Microbial Sensitivity Tests
minimum inhibitory concentration
Genes
mechanism of action
Derivatives
chemical derivatives
energy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans. / Rossignol, Tristan; Kocsis, Béla; Bouquet, Orsolya; Kustos, Ildikó; Kilár, F.; Nyul, Adrien; Jakus, Péter B.; Rajbhandari, Kshitij; Prókai, László; d'Enfert, Christophe; Lóránd, T.

In: PLoS One, Vol. 8, No. 4, e62142, 30.04.2013.

Research output: Contribution to journalArticle

Rossignol, T, Kocsis, B, Bouquet, O, Kustos, I, Kilár, F, Nyul, A, Jakus, PB, Rajbhandari, K, Prókai, L, d'Enfert, C & Lóránd, T 2013, 'Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans', PLoS One, vol. 8, no. 4, e62142. https://doi.org/10.1371/journal.pone.0062142
Rossignol, Tristan ; Kocsis, Béla ; Bouquet, Orsolya ; Kustos, Ildikó ; Kilár, F. ; Nyul, Adrien ; Jakus, Péter B. ; Rajbhandari, Kshitij ; Prókai, László ; d'Enfert, Christophe ; Lóránd, T. / Antifungal Activity of Fused Mannich Ketones Triggers an Oxidative Stress Response and Is Cap1-Dependent in Candida albicans. In: PLoS One. 2013 ; Vol. 8, No. 4.
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