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

• Published in: PloS one Vol. 8; no. 4; p. e62142
• Main Authors: Rossignol, Tristan, Kocsis, Béla, Bouquet, Orsolya, Kustos, Ildikó, Kilár, Ferenc, Nyul, Adrien, Jakus, Péter B, Rajbhandari, Kshitij, Prókai, László, d'Enfert, Christophe, Lóránd, Tamás
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.04.2013; Public Library of Science (PLoS)
• Subjects: Alcohol; Antifungal activity; Antifungal Agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspergillus; Basic-Leucine Zipper Transcription Factors; Basic-Leucine Zipper Transcription Factors - metabolism; Biochemistry; Biology; Biosynthesis; Candida; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candida albicans - growth & development; Candida albicans - metabolism; Candida parapsilosis; CAP1 gene; Cell Cycle Proteins; Cell Cycle Proteins - metabolism; Chemistry; Congeners; Correlation analysis; Dose-Response Relationship, Drug; Fungal infections; Fungal Proteins; Fungal Proteins - metabolism; Fungicides; Gene Expression Profiling; Gene Expression Regulation, Fungal; Gene Expression Regulation, Fungal - drug effects; Hypothesis testing; Immunology; Ketones; Life Sciences; Mannich Bases; Mannich Bases - chemistry; Mannich Bases - pharmacology; Medicine; Microbiology and Parasitology; Minimum inhibitory concentration; Molecular biology; Molecular orbitals; Mutation; Mycology; Oxidative Stress; Oxidative Stress - drug effects; Pharmaceutical sciences; Quantitative Structure-Activity Relationship; Redox properties; Saccharomyces; Saccharomyces cerevisiae; Stress response; Transcription; Yeast; Yeasts; Yeasts - drug effects; Yeasts - metabolism; Fort Worth Texas; Hungary; France; Texas; Candida albicans; Antifungals; Oxidative stress; Aspergillus; Gene prediction; Transcription factors; Ketones; Gene regulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062142

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.