{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T16:21:13Z","timestamp":1783095673526,"version":"3.54.6"},"posted":{"date-parts":[[2026,6,30]]},"group-title":"Microbiology","reference-count":154,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Fungal infections are an escalating global health concern, with rare\n                  <jats:italic>Candida<\/jats:italic>\n                  species posing an urgent threat due to emerging multidrug resistance.\n                  <jats:italic>Clavispora<\/jats:italic>\n                  (\n                  <jats:italic>Candida<\/jats:italic>\n                  )\n                  <jats:italic>lusitaniae<\/jats:italic>\n                  is an uncommon pathogen in which multidrug resistance has been documented during antifungal therapy, yet the selective forces driving this phenotype remain unclear. Here, we show that exposure to the echinocandin micafungin (MCF) alone can select for multidrug resistance in\n                  <jats:italic>C. lusitaniae<\/jats:italic>\n                  . Through controlled evolution experiments we identified individual point mutations in genes encoding ergosterol biosynthesis enzymes (\n                  <jats:italic>ERG<\/jats:italic>\n                  s), sterol trafficking proteins (\n                  <jats:italic>OSH2<\/jats:italic>\n                  ), and the echinocandin drug target (\n                  <jats:italic>FKS1<\/jats:italic>\n                  ) that confer a significant fitness benefit to one or more classes of antifungals. We find that\n                  <jats:italic>ERG3<\/jats:italic>\n                  loss-of-function is the primary and independent driver of pan-antifungal resistance to echinocandins, azoles and polyenes. The\n                  <jats:italic>ERG3<\/jats:italic>\n                  mutants have &lt;1% ergosterol, increased levels of non-toxic sterol intermediates, and increased chitin content, consistent with both cell membrane and cell wall remodeling that enables the fungal pathogen to evade all three drug classes. The convergence of sterol reprogramming and compensatory cell wall remodeling that occurs during adaptation to echinocandin monotherapy can evolve through a single point mutation and parallels our recent case study of acquired multidrug resistance.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>\n                    Multidrug resistance in\n                    <jats:italic>Candida<\/jats:italic>\n                    species severely limits treatment options and increases mortality, particularly in immunocompromised patients. Despite increasing reports of multidrug resistance, the molecular mechanisms driving multidrug resistance remain poorly understood. We find that\n                    <jats:italic>in vitro<\/jats:italic>\n                    MCF exposure alone can drive multidrug resistance in\n                    <jats:italic>C. lusitaniae<\/jats:italic>\n                    via acquisition of\n                    <jats:italic>de novo<\/jats:italic>\n                    point mutations in\n                    <jats:italic>ERG3,<\/jats:italic>\n                    an observation that parallels our recent patient case study. By identifying causative mutations and associated physiological changes, we provide mechanistic insight into the emergence of multidrug resistance and highlight the need for surveillance strategies that account for resistance evolution under echinocandin monotherapy.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.29.735437","type":"posted-content","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T04:50:27Z","timestamp":1782881427000},"source":"Crossref","is-referenced-by-count":0,"title":["Micafungin exposure drives multidrug resistance in\n                  <i>Clavispora lusitaniae<\/i>"],"prefix":"10.64898","author":[{"given":"Elizabeth","family":"Wash","sequence":"first","affiliation":[{"name":"University of Minnesota, Department of Microbiology and Immunology, Minneapolis, Minnesota, USA"},{"name":"University of Minnesota, Molecular, Cellular, and Developmental Biology and Genetics Program, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1678-0796","authenticated-orcid":false,"given":"Nancy E.","family":"Scott","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Microbiology and Immunology, Minneapolis, Minnesota, USA"},{"name":"University of Minnesota, Bioinformatics and Computational Biology Program, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katura","family":"Metzner","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Microbiology and Immunology, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Microbiology and Immunology, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deveney","family":"Da Silva","sequence":"additional","affiliation":[{"name":"Stony Brook University, Department of Microbiology and Immunology, Stony Brook, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivea","family":"Pereira De Sa","sequence":"additional","affiliation":[{"name":"Stony Brook University, Department of Microbiology and Immunology, Stony Brook, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana Akhtar","family":"Usmani","sequence":"additional","affiliation":[{"name":"Stony Brook University, Department of Microbiology and Immunology, Stony Brook, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia Fidelis","family":"Viera De Sa","sequence":"additional","affiliation":[{"name":"Stony Brook University, Department of Microbiology and Immunology, Stony Brook, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8418-3120","authenticated-orcid":false,"given":"Maurizio","family":"Del Poeta","sequence":"additional","affiliation":[{"name":"Stony Brook University, Department of Microbiology and Immunology, Stony Brook, NY, USA"},{"name":"Stony Brook University, Division of Infectious Diseases, Stony Brook, NY, USA"},{"name":"Veterans Affairs Medical Center, Northport, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3298-2400","authenticated-orcid":false,"given":"Anna","family":"Selmecki","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Microbiology and Immunology, Minneapolis, Minnesota, USA"},{"name":"University of Minnesota, Molecular, Cellular, and Developmental Biology and Genetics Program, Minneapolis, Minnesota, USA"},{"name":"University of Minnesota, Bioinformatics and Computational Biology Program, Minneapolis, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070308400567000_2026.06.29.735437v1.1","first-page":"e00464","article-title":"Heterogeneity of Candida bloodstream isolates in an academic medical center and affiliated hospitals","volume":"13","year":"2025","journal-title":"Microbiol Spectr"},{"key":"2026070308400567000_2026.06.29.735437v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa502"},{"key":"2026070308400567000_2026.06.29.735437v1.3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.nmni.2016.07.003","article-title":"Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation","volume":"13","year":"2016","journal-title":"New Microbes New Infect"},{"key":"2026070308400567000_2026.06.29.735437v1.4","unstructured":"CDC. 2024. 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