{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:03:36Z","timestamp":1753877016213,"version":"3.41.2"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T00:00:00Z","timestamp":1646611200000},"content-version":"vor","delay-in-days":34,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"crossref","award":["JP21fk0108135h0902"],"award-info":[{"award-number":["JP21fk0108135h0902"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Candida glabrata is an emerging fungal pathogen in immune-compromised hosts. Previously undetected C. glabrata isolates were successfully recovered from clinical specimens by adding sterols to the growth medium. The clinical isolates are unable to synthesize ergosterol but can take up exogenous sterols under aerobic conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This study characterizes the sterol-auxotrophic C. glabrata strains, examines the mutation(s) in sterol synthesis genes, characterizes the drug susceptibility and evaluates the virulence in a mouse infection model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Drug susceptibility of the C. glabrata strains was evaluated in a sterol-supplemented medium. The coding sequences of the sterol synthesis genes were analysed in six sterol-auxotrophic strains of C. glabrata. The fungal burden of mice infected with C. glabrata strain was determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The sterol-auxotrophic strains showed high-level resistance to both azoles and amphotericin B when sterols were supplied in the test medium. Additionally, the strains harbour missense mutations in either ERG1 or ERG7. Significant differences in fungal burden were not observed between the sterol-auxotrophic strain and the sterol-competent strain with the mice infection models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The sterol-auxotrophic C. glabrata strain investigated in this study seemed to maintain intact virulence, probably due to the supply of exogenous sterols from host organ(s). This suggests that exogenous sterol uptake develops antifungal resistance during infection.<\/jats:p><\/jats:sec>","DOI":"10.1093\/jacamr\/dlac018","type":"journal-article","created":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T12:22:27Z","timestamp":1644841347000},"source":"Crossref","is-referenced-by-count":1,"title":["Exhibition of antifungal resistance by sterol-auxotrophic strains of<i>Candida glabrata<\/i>with intact virulence"],"prefix":"10.1093","volume":"4","author":[{"given":"Minoru","family":"Nagi","sequence":"first","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"},{"name":"Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2361-4748","authenticated-orcid":false,"given":"Koichi","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Faculty of Agriculture, Ryukoku University, 1-5 Yokotani, Seta Oe-cho, Otsu, Shiga 520-2194, Japan"},{"name":"Research Center for Fermentation and Brewing, Ryukoku University, 1-5 Yokotani, Seta Oe-cho, Otsu, Shiga 520-2194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Food Science and Human Nutrition, Faculty of Agriculture, Ryukoku University, 1-5 Yokotani, Seta Oe-cho, Otsu, Shiga 520-2194, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keigo","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironobu","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3 Minami-Tamagaki, Suzuka, Mie 513-8670, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6355-716X","authenticated-orcid":false,"given":"Masahiro","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Yamagoe","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Umeyama","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motoyuki","family":"Sugai","sequence":"additional","affiliation":[{"name":"Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin C.","family":"Hazen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Health System, 2902 DUMC, 116 CARL Building, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitsugu","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,3,7]]},"reference":[{"key":"2022031017585903400_dlac018-B1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/S1473-3099(10)70218-8","article-title":"Emerging opportunistic yeast infections","volume":"11","author":"Miceli","year":"2011","journal-title":"Lancet Infect Dis"},{"key":"2022031017585903400_dlac018-B2","doi-asserted-by":"crossref","first-page":"5623","DOI":"10.1128\/JCM.41.12.5623-5632.2003","article-title":"Comparison of the susceptibilities of Candida spp. to fluconazole and voriconazole in a 4-year global evaluation using disk diffusion","volume":"41","author":"Hazen","year":"2003","journal-title":"J Clin Microbiol"},{"key":"2022031017585903400_dlac018-B3","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1128\/JCM.02117-09","article-title":"Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-year analysis of susceptibilities of Candida species to fluconazole and voriconazole as determined by CLSI standardized disk diffusion","volume":"48","author":"Pfaller","year":"2010","journal-title":"J Clin Microbiol"},{"key":"2022031017585903400_dlac018-B4","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.diagmicrobio.2005.03.001","article-title":"Sterol uptake in Candida glabrata: rescue of sterol auxotrophic strains","volume":"52","author":"Bard","year":"2005","journal-title":"Diagn Microbiol Infect Dis"},{"key":"2022031017585903400_dlac018-B5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.diagmicrobio.2004.12.006","article-title":"Isolation of cholesterol-dependent Candida glabrata from clinical specimens","volume":"52","author":"Hazen","year":"2005","journal-title":"Diagn Microbiol Infect Dis"},{"key":"2022031017585903400_dlac018-B6","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/mmi.12189","article-title":"The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation","volume":"88","author":"Nagi","year":"2013","journal-title":"Mol Microbiol"},{"key":"2022031017585903400_dlac018-B7","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/jac\/dkm321","article-title":"The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum","volume":"60","author":"Nakayama","year":"2007","journal-title":"J Antimicrob Chemother"},{"key":"2022031017585903400_dlac018-B8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1365-2443.2010.01470.x","article-title":"Transcription factors CgUPC2A and CgUPC2B regulate ergosterol biosynthetic genes in Candida glabrata","volume":"16","author":"Nagi","year":"2011","journal-title":"Genes Cells"},{"key":"2022031017585903400_dlac018-B9","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.bbalip.2014.11.002","article-title":"The mannoprotein TIR3 (CAGL0C03872\u2005g) is required for sterol uptake in Candida glabrata","volume":"1851","author":"Inukai","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"2022031017585903400_dlac018-B10","doi-asserted-by":"crossref","first-page":"306","DOI":"10.7883\/yoken.JJID.2009.306","article-title":"Serum or bile affects the in vitro azole susceptibilities of Candida spp","volume":"62","author":"Nagi","year":"2009","journal-title":"Jpn J Infect Dis"},{"key":"2022031017585903400_dlac018-B11","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1128\/AAC.45.11.3037-3045.2001","article-title":"In vitro and in vivo effects of 14alpha-demethylase (ERG11) depletion in Candida glabrata","volume":"45","author":"Nakayama","year":"2001","journal-title":"Antimicrob Agents Chemother"},{"key":"2022031017585903400_dlac018-B12","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1007\/s10156-012-0531-3","article-title":"Serum cholesterol promotes the growth of Candida glabrata in the presence of fluconazole","volume":"19","author":"Nagi","year":"2013","journal-title":"J Infect Chemother"},{"key":"2022031017585903400_dlac018-B13","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1101\/gr.074492.107","article-title":"Velvet: Algorithms for de novo short read assembly using de Bruijn graphs","volume":"18","author":"Zerbino","year":"2008","journal-title":"Genome Res"},{"key":"2022031017585903400_dlac018-B14","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows\u2013Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2022031017585903400_dlac018-B15","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/ng.3036","article-title":"Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications","volume":"46","author":"Rimmer","year":"2014","journal-title":"Nat Genet"},{"key":"2022031017585903400_dlac018-B16","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1080\/15548627.2016.1183080","article-title":"Iron-depletion promotes mitophagy to maintain mitochondrial integrity in pathogenic yeast Candida glabrata","volume":"12","author":"Nagi","year":"2016","journal-title":"Autophagy"},{"key":"2022031017585903400_dlac018-B17","doi-asserted-by":"crossref","first-page":"45226","DOI":"10.1074\/jbc.M407600200","article-title":"ATP-binding cassette (ABC) transporters mediate nonvesicular, raft-modulated sterol movement from the plasma membrane to the endoplasmic reticulum","volume":"279","author":"Li","year":"2004","journal-title":"J Biol Chem"},{"key":"2022031017585903400_dlac018-B18","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1111\/febs.12015","article-title":"Accumulation of squalene is associated with the clustering of lipid droplets","volume":"279","author":"Ta","year":"2012","journal-title":"FEBS J"},{"key":"2022031017585903400_dlac018-B19","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1006\/bbrc.1995.1272","article-title":"Mode of action and resistance to azole antifungals associated with the formation of 14\u03b1-methylergosta-8,24(28)-dien-3\u03b2,6\u03b1-diol","volume":"207","author":"Kelly","year":"1995","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031017585903400_dlac018-B20","doi-asserted-by":"crossref","first-page":"5188","DOI":"10.1021\/acs.biochem.9b00835","article-title":"The amphotericin B\u2013ergosterol complex spans a lipid bilayer as a single-length assembly","volume":"58","author":"Yamamoto","year":"2019","journal-title":"Biochemistry"},{"key":"2022031017585903400_dlac018-B21","doi-asserted-by":"crossref","first-page":"17029","DOI":"10.1038\/s41598-019-53517-3","article-title":"Modes of the antibiotic activity of amphotericin B against Candida albicans","volume":"9","author":"Grela","year":"2019","journal-title":"Sci Rep"}],"container-title":["JAC-Antimicrobial Resistance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/4\/1\/dlac018\/42807181\/dlac018.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/4\/1\/dlac018\/42807181\/dlac018.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T12:53:16Z","timestamp":1700225596000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jacamr\/article\/doi\/10.1093\/jacamr\/dlac018\/6543370"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,1]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,2,28]]}},"URL":"https:\/\/doi.org\/10.1093\/jacamr\/dlac018","relation":{},"ISSN":["2632-1823"],"issn-type":[{"type":"electronic","value":"2632-1823"}],"subject":[],"published-other":{"date-parts":[[2022,2,1]]},"published":{"date-parts":[[2022,2,1]]},"article-number":"dlac018"}}