{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:11:48Z","timestamp":1787796708528,"version":"build-2784847793"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012521","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000}}],"reference-count":67,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["5R01AI109025"],"award-info":[{"award-number":["5R01AI109025"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Invasive fungal infections are associated with high mortality, which is exacerbated by the limited antifungal drug armamentarium and increasing antifungal drug resistance. Echinocandins are a frontline antifungal drug class targeting \u03b2-glucan synthase (GS), a fungal cell wall biosynthetic enzyme. Echinocandin resistance is generally low but increasing in species like <jats:italic>Candida glabrata<\/jats:italic>, an opportunistic yeast pathogen colonizing human mucosal surfaces. Mutations in GS-encoding genes (<jats:italic>FKS1<\/jats:italic> and <jats:italic>FKS2<\/jats:italic> in <jats:italic>C<\/jats:italic>. <jats:italic>glabrata<\/jats:italic>) are strongly associated with clinical echinocandin failure, but epidemiological studies show that other, as yet unidentified factors also influence echinocandin susceptibility. Furthermore, although the gut is known to be an important reservoir for emergence of drug-resistant strains, the evolution of resistance is not well understood. Here, we studied the evolutionary dynamics of <jats:italic>C<\/jats:italic>. <jats:italic>glabrata<\/jats:italic> colonizing the gut of immunocompetent mice during treatment with caspofungin, a widely-used echinocandin. Whole genome and amplicon sequencing revealed rapid genetic diversification of this <jats:italic>C<\/jats:italic>. <jats:italic>glabrata<\/jats:italic> population during treatment and the emergence of both drug target (<jats:italic>FKS2<\/jats:italic>) and non-drug target mutations, the latter predominantly in the <jats:italic>FEN1<\/jats:italic> gene encoding a fatty acid elongase functioning in sphingolipid biosynthesis. The <jats:italic>fen1<\/jats:italic> mutants displayed high fitness in the gut specifically during caspofungin treatment and contained high levels of phytosphingosine, whereas genetic depletion of phytosphingosine by deletion of <jats:italic>YPC1<\/jats:italic> gene hypersensitized the wild type strain to caspofungin and was epistatic to <jats:italic>fen1\u0394<\/jats:italic>. Furthermore, high resolution imaging and mass spectrometry showed that reduced caspofungin susceptibility in <jats:italic>fen1\u0394<\/jats:italic> cells was associated with reduced caspofungin binding to the plasma membrane. Finally, we identified several different <jats:italic>fen1<\/jats:italic> mutations in clinical <jats:italic>C<\/jats:italic>. <jats:italic>glabrata<\/jats:italic> isolates, which phenocopied the <jats:italic>fen1\u0394<\/jats:italic> mutant, causing reduced caspofungin susceptibility. These studies reveal new genetic and molecular determinants of clinical caspofungin susceptibility and illuminate the dynamic evolution of drug target and non-drug target mutations reducing echinocandin efficacy in patients colonized with <jats:italic>C<\/jats:italic>. <jats:italic>glabrata<\/jats:italic>.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012521","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T17:31:04Z","timestamp":1725903064000},"page":"e1012521","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Evolutionary dynamics in gut-colonizing Candida glabrata during caspofungin therapy: Emergence of clinically important mutations in sphingolipid biosynthesis"],"prefix":"10.1371","volume":"20","author":[{"given":"Yasmine","family":"Hassoun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel A.","family":"Aptekmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail V.","family":"Keniya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Y.","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Alayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Novi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Quinteros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Firat","family":"Kaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Zimmerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego H.","family":"Caceres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy A.","family":"Chow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Perlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3655-0963","authenticated-orcid":true,"given":"Erika","family":"Shor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"issue":"1","key":"ppat.1012521.ref001","doi-asserted-by":"crossref","first-page":"ofab593","DOI":"10.1093\/ofid\/ofab593","article-title":"Prevalence and Healthcare Burden of Fungal Infections in the United States, 2018","volume":"9","author":"E Rayens","year":"2022","journal-title":"Open Forum Infect Dis"},{"issue":"1","key":"ppat.1012521.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.idc.2015.10.004","article-title":"The Global Burden of 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