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We conducted comprehensive mechanistic studies to identify the molecular targets and pathways affected by amantelide A. Our investigations relied on chemical structure similarities with compounds of known mechanisms, yeast knockout mutants, yeast chemogenomic profiling, and direct biochemical and biophysical methods. We established that amantelide A exerts its antifungal action by binding to ergosterol\u2010containing membranes followed by pore formation and cell death, a mechanism partially shared with polyene antifungals. Binding assays demonstrated that amantelide A also binds to membranes containing epicholesterol or mammalian cholesterol, thus suggesting that the cytotoxicity to mammalian cells might be due to its affinity to cholesterol\u2010containing membranes. However, membrane interactions were not completely dependent on sterols. Yeast chemogenomic profiling suggested additional direct or indirect effects on actin. Accordingly, we performed actin polymerization assays, which suggested that amantelide A also promotes actin polymerization in cell\u2010free systems. However, the C\u201033 acetoxy derivative amantelide B showed a similar effect on actin dynamics in vitro but no significant activity against yeast. Overall, these studies suggest that the membrane effects are the most functionally relevant for amantelide A mechanism of action.<\/jats:p>","DOI":"10.1002\/cbic.202000685","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T03:18:25Z","timestamp":1612322305000},"page":"1790-1799","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Genomic and Targeted Approaches Unveil the Cell Membrane as a Major Target of the Antifungal Cytotoxin Amantelide A"],"prefix":"10.1002","volume":"22","author":[{"given":"Lobna A.","family":"Elsadek","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry University of Florida  1345 Center Drive Gainesville FL 32610 USA"},{"name":"Center for Natural Products,Drug Discovery and Development (CNPD3) University of Florida  1345 Center Drive Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James H.","family":"Matthews","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Florida  1345 Center Drive Gainesville FL 32610 USA"},{"name":"Center for Natural Products,Drug Discovery and Development (CNPD3) University of Florida  1345 Center Drive Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of System Chemotherapy and Molecular Sciences Division of Bioinformatics and Chemical Genomics Graduate School of Pharmaceutical Sciences Kyoto University Sakyo-ku  Kyoto 606-8501 Japan"},{"name":"Department of Biotechnology Graduate School of Agricultural and Life Sciences University of Tokyo  Bunkyo-ku Tokyo 113-8657 Japan"},{"name":"Collaborative Research Institute for Innovative Microbiology University of Tokyo  1-1-1 Yayoi, Bunkyo-ku Tokyo 113-8657 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nakatani","sequence":"additional","affiliation":[{"name":"Department of System Chemotherapy and Molecular Sciences Division of Bioinformatics and Chemical Genomics Graduate School of Pharmaceutical Sciences Kyoto University Sakyo-ku  Kyoto 606-8501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Airi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of System Chemotherapy and Molecular Sciences Division of Bioinformatics and Chemical Genomics Graduate School of Pharmaceutical Sciences Kyoto University Sakyo-ku  Kyoto 606-8501 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongjun","family":"Gu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Biotechnology Research University of Florida  2033 Mowry Road Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danmeng","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Florida  1345 Center Drive Gainesville FL 32610 USA"},{"name":"Center for Natural Products,Drug Discovery and Development (CNPD3) University of Florida  1345 Center Drive Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilibeth A.","family":"Salvador\u2010Reyes","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Florida  1345 Center Drive Gainesville FL 32610 USA"},{"name":"Marine Science Institute College of Science University of the Philippines Diliman  Quezon City 1100 Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie J.","family":"Paul","sequence":"additional","affiliation":[{"name":"Smithsonian Marine Station  701 Seaway Drive, Ft. 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