{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:48:55Z","timestamp":1792651735830,"version":"4.5.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,2,14]]},"abstract":"<jats:p>\n                    Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings (\n                    <jats:italic>i<\/jats:italic>\n                    ) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, (\n                    <jats:italic>ii<\/jats:italic>\n                    ) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and (\n                    <jats:italic>iii<\/jats:italic>\n                    ) suggest that the capacity for AmB to form protein-like ion channels might be separable from its cytocidal effects.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1117280109","type":"journal-article","created":{"date-parts":[[2012,1,18]],"date-time":"2012-01-18T00:37:35Z","timestamp":1326847055000},"page":"2234-2239","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":571,"title":["Amphotericin primarily kills yeast by simply binding ergosterol"],"prefix":"10.1073","volume":"109","author":[{"given":"Kaitlyn C.","family":"Gray","sequence":"first","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Palacios","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Dailey","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew M.","family":"Endo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice E.","family":"Uno","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon C.","family":"Wilcock","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin D.","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,1,17]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/262698a0"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1015023108"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja075739o"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.1996.270.3.L386"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2001.281.1.L24"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.2001.281.5.L1164"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja029372t"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.321.5887.356"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1159746"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.2007\/010405-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021585"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1039\/b820743g"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1351\/PAC-CON-08-08-37"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(02)00581-3"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4157(86)90002-X"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(74)90332-0"},{"key":"e_1_3_3_17_2","first-page":"377","volume-title":"Lipid Bilayers and Antibiotics","author":"Finkelstein A","year":"1973","unstructured":"A Finkelstein, R Holz, Aqueous pores created in thin lipid membranes by the polyene antibiotics nystatin and AmB membranes. 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