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

• Published in: http://www.plosone.org Vol. 4
• Main Authors: Rossignol , Tristan (INRAInstitut Pasteur de Paris, ParisParis(France). USC 2019Dept Genomes & Genet), Kocsis , Bela (Pecs University, Pecs(Hongrie). Dept Med Microbiol & Immunol, Fac Med), Bouquet , Orsolya (Pecs University, Pecs(Hongrie). Inst Bioanal, Fac Med), Kustos , Ildiko (Alder Hey Childrens NHS Fdn Trust, Liverpool, Merseyside(Royaume Uni). Dept Microbiol), Kilar , Ferenc (Pecs University, Pecs(Hongrie). Inst Bioanal, Fac Med), Nyul , Adrien (Pecs University, Pecs(Hongrie). Dept Med Microbiol & Immunol, Fac Med), Jakus , Peter B. (Pecs University, Pecs(Hongrie). Dept Biochem & Med Chem, Fac Med), Rajbhandari , Kshitij (University of North Texas, Ft Worth(Etats-Unis). Hlth Sci Ctr, Dept Mol Biol & Immunol), Prokai , Laszlo (University of North Texas, Ft Worth(Etats-Unis). Hlth Sci Ctr, Dept Mol Biol & Immunol), d'Enfert , Christophe (INRAInstitut Pasteur, ParisParis(France). USC 2019Unite Biol & Pathogenicite Fong, Dept Genomes & Genet), Lorand , Tamas (Pecs University, Pecs(Hongrie). Dept Biochem & Med Chem, Fac Med)
• Format: Publication
• Language: English
• Published: 2013

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 (MIC(90)s) ranging from 0.8 to 6 mg/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.