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. 2013 Apr 30;8(4):e62142.
doi: 10.1371/journal.pone.0062142. Print 2013.

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

Tristan Rossignol  1 , Béla Kocsis, Orsolya Bouquet, Ildikó Kustos, Ferenc Kilár, Adrien Nyul, Péter B Jakus, Kshitij Rajbhandari, László Prókai, Christophe d'Enfert, Tamás Lóránd
Affiliations

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

Tristan Rossignol et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Chemical structures of the fused Mannich ketones investigated.
Figure 2
Figure 2. Chemical structure of the aminoalcohols investigated.
Figure 3
Figure 3. QSAR analysis of Mannich ketones for antifungal activity towards Candida albicans.
Comparison of the experimental and calculated negative logarithms of the minimum inhibitory concentration from QSAR (pMICExp and pMICCalc) of Mannich ketones in C. albicans was based on the equation considering three descriptors: energy of the lowest unoccupied molecular orbital (LUMO, eV) solvent-accessible surface area (SASE, Å2), and ionization potential (IP, eV) (Table 2). Green triangles: Fused Mannich ketones reported here; Magenta squares: unsaturated cyclic Mannich ketones and aminoalcohols reported earlier .
Figure 4
Figure 4. Growth kinetics in 96-well microtiter plates of C. albicans strains exposed to various concentrations of compound 2.
A. Representative growth kinetics of BWP17 and cap1Δ/Δ strains exposed to decreasing concentrations of compound 2 in SD minimal medium. B. Representative growth kinetics of BWP17, cap1Δ/Δ and CAP1 overexpression strains in inducible medium (YNB-casa) exposed to 12.5 µg/mL compound 2. C. Representative growth kinetics of several transcription factor mutants and parent strains in SD minimal medium exposed to 6.25 µg/mL compound 2.
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