Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens.

Details

Serval ID
serval:BIB_C14E76F5E4D0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens.
Journal
Antimicrobial agents and chemotherapy
Author(s)
Dorsaz S., Snäkä T., Favre-Godal Q., Maudens P., Boulens N., Furrer P., Ebrahimi S.N., Hamburger M., Allémann E., Gindro K., Queiroz E.F., Riezman H., Wolfender J.L., Sanglard D.
ISSN
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
09/2017
Peer-reviewed
Oui
Volume
61
Number
9
Pages
1-23
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
<i>Candida albicans</i> is a major cause of fungal diseases in humans, and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small-scale screening of a library of 199 natural plant compounds (i.e., natural products [NPs]). <i>In vitro</i> susceptibility profiling experiments identified 33 NPs with activity against <i>C. albicans</i> (MIC <sub>50</sub> s ≤ 32 μg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato ( <i>Solanum lycopersicum</i> ) and exhibited high levels of fungistatic activity against <i>Candida</i> species (MIC <sub>50</sub> s ≤ 1 μg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated <i>C. albicans</i> cells revealed a major alteration (upregulation) in the expression of ergosterol genes, suggesting that the ergosterol pathway is targeted by this NP. Consistent with this transcriptional response, analysis of the sterol content of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) activity but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in <i>Saccharomyces cerevisiae</i> coupled with whole-genome sequencing identified 2 nonsynonymous mutations in <i>ERG6</i> (amino acids D249G and G132D) responsible for tomatidine resistance. Our results therefore unambiguously identified Erg6, a C-24 sterol methyltransferase absent in mammals, to be the main direct target of tomatidine. We tested the <i>in vivo</i> efficacy of tomatidine in a mouse model of <i>C. albicans</i> systemic infection. Treatment with a nanocrystal pharmacological formulation successfully decreased the fungal burden in infected kidneys compared to the fungal burden achieved by the use of placebo and thus confirmed the potential of tomatidine as a therapeutic agent.

Keywords
Animals, Antifungal Agents/pharmacology, Biological Products/pharmacology, Candida albicans/drug effects, Candidiasis/drug therapy, Candidiasis/microbiology, Cell Line, Tumor, Drug Resistance, Fungal/drug effects, Drug Resistance, Fungal/genetics, Ergosterol/pharmacology, Female, Fluconazole/pharmacology, Genes, Fungal/genetics, HeLa Cells, Humans, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests/methods, Plant Extracts/pharmacology, Saccharomyces cerevisiae/genetics, Tomatine/analogs & derivatives, Tomatine/pharmacology, antifungal agents, antifungal therapy, natural products, sterol biosynthesis
Pubmed
Web of science
Open Access
Yes
Create date
27/07/2017 14:00
Last modification date
20/08/2019 16:36
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