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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]).\n            <jats:italic>In vitro<\/jats:italic>\n            susceptibility profiling experiments identified 33 NPs with activity against\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            (MIC\n            <jats:sub>50<\/jats:sub>\n            s \u2264 32 \u03bcg\/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato (\n            <jats:named-content content-type=\"genus-species\">Solanum lycopersicum<\/jats:named-content>\n            ) and exhibited high levels of fungistatic activity against\n            <jats:named-content content-type=\"genus-species\">Candida<\/jats:named-content>\n            species (MIC\n            <jats:sub>50<\/jats:sub>\n            s \u2264 1 \u03bcg\/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            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\n            <jats:named-content content-type=\"genus-species\">Saccharomyces cerevisiae<\/jats:named-content>\n            coupled with whole-genome sequencing identified 2 nonsynonymous mutations in\n            <jats:italic>ERG6<\/jats:italic>\n            (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\n            <jats:italic>in vivo<\/jats:italic>\n            efficacy of tomatidine in a mouse model of\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            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.\n          <\/jats:p>","DOI":"10.1128\/aac.00829-17","type":"journal-article","created":{"date-parts":[[2017,7,4]],"date-time":"2017-07-04T00:40:52Z","timestamp":1499128852000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":47,"title":["Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens"],"prefix":"10.1128","volume":"61","author":[{"given":"St\u00e9phane","family":"Dorsaz","sequence":"first","affiliation":[{"name":"Institute of Microbiology, University of Lausanne, and Lausanne University Hospital, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiia","family":"Sn\u00e4k\u00e4","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University of Lausanne, and Lausanne University Hospital, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Favre-Godal","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Maudens","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Boulens","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Furrer","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samad Nejad","family":"Ebrahimi","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hamburger","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"All\u00e9mann","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Gindro","sequence":"additional","affiliation":[{"name":"Agroscope, Strategic Research Division Plant Protection, Mycology, and Biotechnology, Nyon, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emerson Ferreira","family":"Queiroz","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Riezman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Wolfender","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, EPGL, University of Geneva-University of Lausanne, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5244-4178","authenticated-orcid":false,"given":"Dominique","family":"Sanglard","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University of Lausanne, and Lausanne University Hospital, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2010.02.004"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccm.2009.02.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11908-006-0019-3"},{"key":"e_1_3_3_5_2","first-page":"349","volume-title":"Candida and candidiasis","author":"Sanglard D","year":"2002","unstructured":"Sanglard D BilleJ CalderoneR. 2002. 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