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

Dorsaz, Stéphane; Snäkä, Tiia; Favre-Godal, Quentin; Maudens, Pierre Marc Xavier; Boulens, Nathalie; Furrer, Pascal; Ebrahimi, Samad Nejad; Hamburger, Matthias; Allémann, Eric; Gindro, Katia; Ferreira Queiroz, Emerson; Riezman, Howard; Wolfender, Jean-Luc; Sanglard, Dominique

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Title		Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens
Authors		Dorsaz, Stéphane Snäkä, Tiia Favre-Godal, Quentin Maudens, Pierre Marc Xavier Boulens, Nathalie Furrer, Pascal Ebrahimi, Samad Nejad Hamburger, Matthias Allémann, Eric Gindro, Katia Ferreira Queiroz, Emerson Riezman, Howard Wolfender, Jean-Luc Sanglard, Dominique show all authors [1 - 14]
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 agents — Natural products — Sterol biosynthesis — Antifungal therapy
Identifiers		DOI: 10.1128/AAC.00829-17 PMID: 28674054
Full text		Article (Author postprint) (849 Kb) - Free access Other version: http://aac.asm.org/lookup/doi/10.1128/AAC.00829-17
Structures		Faculté des sciences / Section des sciences pharmaceutiques Faculté des sciences / Section de chimie et biochimie / Département de biochimie
Research groups		Phytochimie et produits naturels bioactifs Technologie pharmaceutique Groupe Riezman
Citation (ISO format)		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