{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:52:12Z","timestamp":1790610732450,"version":"4.1.0"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Echinocandins, which target the fungal \u03b2-1,3-glucan synthase (Fks), are essential for treating invasive fungal infections, yet resistance is increasingly reported. While resistance typically arises through mutations in Fks hotspots, emerging evidence suggests a contributing role of changes in membrane sterol composition due to\n                      <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                      mutations. Here, we present a clinical case of\n                      <jats:italic toggle=\"yes\">Nakaseomyces glabratus<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Candida glabrata<\/jats:italic>\n                      ) in which combined mutations in\n                      <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      , but not\n                      <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                      alone, appear to confer echinocandin resistance. Integrated analyses reveal a recurrent association between Erg3 loss-of-function and echinocandin resistance mediated by Fks variation across\n                      <jats:italic toggle=\"yes\">Candida<\/jats:italic>\n                      species, but exclude Erg3 loss-of-function as an independent resistance mechanism. Advances in Fks structural biology and insights into echinocandin-Fks interactions support a model of epistatic cross-talk between membrane sterols and Fks function. Understanding this interaction is crucial, as it may underlie not only acquired echinocandin resistance but also the broader development of multidrug resistance across major antifungal drug classes.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        A clinical case in which the combination of variation in a \u03b2\u20111,3\u2011glucan synthase-encoding gene (\n                        <jats:italic toggle=\"yes\">FKS2<\/jats:italic>\n                        ) and the sterol desaturase-encoding gene\u202f\n                        <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                        seems to underlie echinocandin resistance, prompted us to hypothesize that membrane sterol changes may modulate, rather than independently cause, Fks\u2011linked resistance. We were able to explore this hypothesis due to recent developments in the field, such as the release of the FungAMR database, which enables global co\u2011occurrence analyses; AI\u2011driven variant effect predictors such as Evolutionary Scale Modeling (ESM) that can explore the impact of thousands of\n                        <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                        alleles; the cryo\u2011EM resolution of the Fks1 protein; and the first mechanistic model of echinocandin\u2011Fks1 binding. Together, these advances provide the structural and computational framework needed to delineate our hypothesis that specific sterol variants might influence \u03b2\u20111,3\u2011glucan synthase function and drug binding. Further surveillance of this potentially epistatic interaction can be of significant clinical importance amid rising multidrug\u2011resistant infections, as overlooking such interactions could lead to under\u2011calling resistance and misguided therapy.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01419-25","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T13:00:11Z","timestamp":1757422811000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Epistasis at the cell surface: what is the role of Erg3 loss-of-function in acquired echinocandin 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