Document Detail

Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
MedLine Citation:
PMID:  23646117     Owner:  NLM     Status:  MEDLINE    
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.
Tristan Rossignol; Béla Kocsis; Orsolya Bouquet; Ildikó Kustos; Ferenc Kilár; Adrien Nyul; Péter B Jakus; Kshitij Rajbhandari; László Prókai; Christophe d'Enfert; Tamás Lóránd
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-04-30
Journal Detail:
Title:  PloS one     Volume:  8     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2013  
Date Detail:
Created Date:  2013-05-06     Completed Date:  2013-11-26     Revised Date:  2013-12-02    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e62142     Citation Subset:  IM    
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MeSH Terms
Antifungal Agents / chemistry,  pharmacology*
Basic-Leucine Zipper Transcription Factors / metabolism*
Candida albicans / drug effects*,  genetics,  growth & development,  metabolism*
Cell Cycle Proteins / metabolism*
Dose-Response Relationship, Drug
Fungal Proteins / metabolism*
Gene Expression Profiling
Gene Expression Regulation, Fungal / drug effects
Mannich Bases / chemistry,  pharmacology*
Oxidative Stress / drug effects*
Quantitative Structure-Activity Relationship
Yeasts / drug effects,  metabolism
Reg. No./Substance:
0/Antifungal Agents; 0/Basic-Leucine Zipper Transcription Factors; 0/CAP1 protein, Candida albicans; 0/Cell Cycle Proteins; 0/Fungal Proteins; 0/Mannich Bases

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