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Title

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

Authors
Dorsaz, Stéphane
Snäkä, Tiia
Ebrahimi, Samad Nejad
Hamburger, Matthias
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Published in Antimicrobial Agents and Chemotherapy. 2017, vol. 61, no. 9, p. e00829-17
Abstract Candida albicans 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 199 natural plant compounds (NPs) library. In vitro susceptibility profiling experiments identified 33 NPs with activity against C. albicans (MIC50 ≤ 32 µg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from Solanum lycopersicum (tomato) and exhibited high fungistatic activity against Candida species (MIC50 ≤ 1 µg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of C. albicans tomatidine-treated cells revealed a major alteration (upregulation) of ergosterol genes suggesting that the ergosterol pathway was targeted by this NP. Consistent with this transcriptional response, sterol content analysis of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in Saccharomyces cerevisiae coupled with whole genome sequencing identified 2 non-synonymous mutations in ERG6 (amino acids: D249G and G132D) responsible for tomatidine resistance. Our results therefore identified unambiguously Erg6, a sterol C-24 methyltransferase absent in mammals, as the main direct target of tomatidine. We tested the in vivo efficacy of tomatidine in a mouse model of C. albicans systemic infection. Treatment with a nano-crystal pharmacological formulation successfully decreased the fungal burden in infected kidneys as compared to placebo and thus confirmed the potential of tomatidine as a therapeutic agent
Keywords Antifungal agentsNatural productsSterol biosynthesisAntifungal therapy
Identifiers
PMID: 28674054
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Structures
Research groups Phytochimie et produits naturels bioactifs
Technologie pharmaceutique
Groupe Riezman
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DORSAZ, Stéphane et al. Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens. In: Antimicrobial Agents and Chemotherapy, 2017, vol. 61, n° 9, p. e00829-17. https://archive-ouverte.unige.ch/unige:103514

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Deposited on : 2018-04-13

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