title: Antifungal activity of fused Mannich ketones triggers an oxidative stress response and is Cap1-dependent in Candida albicans.
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.
authors: Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France.
authors: Tristan
authors: T
authors: Rossignol
authors: Béla
authors: B
authors: Kocsis
authors: Orsolya
authors: O
authors: Bouquet
authors: Ildikó
authors: I
authors: Kustos
authors: Ferenc
authors: F
authors: Kilár
authors: Adrien
authors: A
authors: Nyul
authors: Péter B
authors: PB
authors: Jakus
authors: Kshitij
authors: K
authors: Rajbhandari
authors: László
authors: L
authors: Prókai
authors: Christophe
authors: C
authors: d'Enfert
authors: Tamás
authors: T
authors: Lóránd
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005656:Fungal Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D008352:Mannich Bases / Q000737:chemistry / Q000494:pharmacology*; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D015003:Yeasts / Q000187:drug effects / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D050976:Basic-Leucine Zipper Transcription Factors; C426523:CAP1 protein, Candida albicans; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D008352:Mannich Bases
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