{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:34Z","timestamp":1785407494229,"version":"3.56.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"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":[[2026,6,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The emergence of multidrug-resistant fungal pathogens from urinary tract infections (UTIs) poses a growing challenge in clinical settings. Here, we report a case of a complicated UTI caused by\n                      <jats:italic toggle=\"yes\">Nakaseomyces glabratus<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Candida glabrata<\/jats:italic>\n                      ) that progressed to urosepsis, leading to the emergence of an isolate carrying simultaneous loss-of-function mutations in\n                      <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ERG11,<\/jats:italic>\n                      and abrogated ergosterol biosynthesis. Together with a missense mutation in\u202f\n                      <jats:italic toggle=\"yes\">FUR1<\/jats:italic>\n                      \u2014likely responsible for 5-fluorocytosine resistance\u2014this constellation confers resistance to all viable UTI antifungals: azoles, amphotericin\u202fB, and flucytosine. Engineered\n                      <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                      \u0394\n                      <jats:italic toggle=\"yes\">+ ERG11<\/jats:italic>\n                      \u0394 strains recapitulated this multidrug resistance and revealed profound fitness costs that come with it, challenging the assumption that high-cost mutations are unlikely to persist during infection. Among fitness trade-offs, we detected collateral sensitivity to nitroxoline, a commonly used urinary tract antibiotic with potent antifungal activity and a unique mechanism of action. This study provides the first clinical evidence of an elusive mechanism of hyper-multidrug resistance in\n                      <jats:italic toggle=\"yes\">N. glabratus<\/jats:italic>\n                      and highlights nitroxoline as a promising repurposing agent for treating multidrug-resistant fungal infections of the urinary tract.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Evolutionary theory states that fitness determines survival. In a drug-treatment environment, resistance increases fitness, but it often comes at a cost, such as slower growth or reduced stress tolerance. If these costs are too severe, they can undermine virulence, making resistance unlikely to persist. Our study challenges this assumption. We describe the first clinical case of\n                      <jats:italic toggle=\"yes\">Nakaseomyces glabratus<\/jats:italic>\n                      evolving multidrug resistance through loss-of-function mutations in\n                      <jats:italic toggle=\"yes\">ERG3<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ERG11<\/jats:italic>\n                      , despite severe fitness trade-offs. This case suggests that certain infection niches, such as the urinary tract, can provide conditions where even highly impaired yet resistant strains persist under strong antifungal pressure. Importantly, we show that this extreme resistance induces collateral sensitivity to nitroxoline, a urinary tract infection antibiotic with potent antifungal activity and a unique mechanism of action. These findings open promising therapeutic avenues to counter multidrug-resistant fungal infections of the urinary tract.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00588-26","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T13:00:45Z","timestamp":1779282045000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Urosepsis by multidrug-resistant\n                    <i>Nakaseomyces\u202fglabratus<\/i>\n                    with non-functional Erg3 and Erg11\u2014do collateral sensitivity and a unique mode of action make nitroxoline a viable UTI antifungal?"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1507-3475","authenticated-orcid":true,"given":"Hans","family":"Carolus","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]},{"name":"D\u00e9partement de Biochimie, de Microbiologie et de Bio-informatique, Facult\u00e9 des Sciences et de G\u00e9nie, Universit\u00e9 Laval","place":["Qu\u00e9bec City, Canada"]},{"name":"Institut de Biologie Int\u00e9grative et des Syst\u00e8mes (IBIS), Universit\u00e9 Laval","place":["Qu\u00e9bec City, Canada"]},{"name":"PROTEO, Le regroupement qu\u00e9b\u00e9cois de recherche sur la fonction, l\u2019ing\u00e9nierie et les applications des prot\u00e9ines, Universit\u00e9 Laval","place":["Qu\u00e9bec City, Canada"]},{"name":"Centre de Recherche en Infectiologie (CRI), Universit\u00e9 Laval","place":["Qu\u00e9bec City, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav","family":"Biriukov","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03kpps236","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology","place":["Barcelona, Spain"]},{"name":"Barcelona Supercomputing Centre (BSC-CNS)","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Vreys","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Lobo Romero","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Paulo","family":"Herrera Avila","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050d0xx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, Ziekenhuis Aan de Stroom (ZAS) Antwerpen","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Vergauwen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1767-0831","authenticated-orcid":true,"given":"Dimitrios","family":"Sofras","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5591-0595","authenticated-orcid":true,"given":"Jana","family":"Nysten","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giel","family":"Vanreppelen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Molecular Cell Biology, Department of Biology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lore","family":"Vinken","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basil","family":"Britto Xavier","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050d0xx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, Ziekenhuis Aan de Stroom (ZAS) Antwerpen","place":["Antwerp, Belgium"]},{"id":[{"id":"https:\/\/ror.org\/012p63287","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Microbiology and Infection Prevention, University of Groningen","place":["Groningen, the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0019-1735","authenticated-orcid":true,"given":"Toni","family":"Gabald\u00f3n","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03kpps236","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology","place":["Barcelona, Spain"]},{"name":"Barcelona Supercomputing Centre (BSC-CNS)","place":["Barcelona, Spain"]},{"id":[{"id":"https:\/\/ror.org\/0371hy230","id-type":"ROR","asserted-by":"publisher"}],"name":"Catalan Institution for Research and Advanced Studies (ICREA)","place":["Barcelona, Spain"]},{"name":"CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8668-1350","authenticated-orcid":true,"given":"Katrien","family":"Lagrou","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, KU Leuven","place":["Leuven, Belgium"]},{"id":[{"id":"https:\/\/ror.org\/0424bsv16","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Laboratory Medicine and National Reference Center for Mycosis, UZ Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinout","family":"Naesens","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/050d0xx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, Ziekenhuis Aan de Stroom (ZAS) Antwerpen","place":["Antwerp, Belgium"]},{"id":[{"id":"https:\/\/ror.org\/050d0xx93","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Microbiology and Infection Prevention, Ziekenhuis Aan de Stroom Antwerp","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-897X","authenticated-orcid":true,"given":"Patrick","family":"Van Dijck","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05f950310","id-type":"ROR","asserted-by":"publisher"}],"name":"KU Leuven One Health Institute, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00692-8"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12281-023-00455-3"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/mmy\/myae041"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.5173\/ceju.2015.01.474"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1086\/510432"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ933"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03333-20"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001692"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01854-z"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof6040321"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.12.2708"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.8.2404-2412.2003"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00555-13"},{"key":"e_1_3_5_15_2","unstructured":"CLSI. 2022. CLSI M57S: epidemiological cutoff values for antifungal susceptibility testing. Available from: https:\/\/clsi.org\/standards\/products\/microbiology\/documents\/m57s"},{"key":"e_1_3_5_16_2","unstructured":"EUCAST. 2024. Breakpoint tables for interpretation of MICs for antifungal agents version 11.0 valid from 2024-12-02. Available from: https:\/\/www.eucast.org\/fileadmin\/src\/media\/PDFs\/EUCAST_files\/AFST\/Clinical_breakpoints\/AFST_BP_v11.0.pdf"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-023-01547-z"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2022.06.082"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-16-S8-S1"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.22.10915"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq695"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof7110909"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/yea.1387"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-025-02084-7"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02265-21"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2016.03.014"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2021.06.035"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01811-w"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1039\/C4MD00284A"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mycmed.2023.101411"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-58730-5"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.2165\/11538110-000000000-00000"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01305-20"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01121-14"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.02173"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-5793(96)01360-9"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.00311-23"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01419-25"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01585"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1534\/g3.117.042887"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01628-18"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.15.68"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000796"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05685"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009940"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msv006"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-022-02737-4"},{"key":"e_1_3_5_48_2","unstructured":"Andrews S. 2010. FastQC: a quality control tool for high throughput sequence data. Available from: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giab008"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","unstructured":"Poplin R Ruano-Rubio V DePristo MA Fennell TJ Carneiro MO Van der Auwera GA Kling DE Gauthier LD Levy-Moonshine A Roazen D Shakir K Thibault J Chandran S Whelan C Lek M Gabriel S Daly MJ Neale B MacArthur DG Banks E. 2018. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv. doi:10.1101\/201178","DOI":"10.1101\/201178"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","unstructured":"Garisson E Marth G. 2012. Haplotype-based variant detection from short-read sequencing. arXiv. doi:10.48550\/arXiv.1207.3907","DOI":"10.48550\/arXiv.1207.3907"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks186"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.005"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00588-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00588-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:05:16Z","timestamp":1782392716000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.00588-26"}},"subtitle":[],"editor":[{"given":"Yong-Sun","family":"Bahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":54,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6,10]]}},"alternative-id":["10.1128\/mbio.00588-26"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00588-26","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"assertion":[{"value":"2026-03-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00588-26"}}