{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:32:56Z","timestamp":1787790776557,"version":"build-2784847793"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["Grant No. 82102454"],"award-info":[{"award-number":["Grant No. 82102454"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Invasive candidiasis poses a growing threat to global public health, compounded by the scarcity of effective antifungal treatments. Miltefosine exhibits broad-spectrum antifungal activity, yet its mechanisms of antifungal action and the development of resistance remain poorly understood. Here, we first generated miltefosine-resistant strains of\n                      <jats:italic toggle=\"yes\">Candida glabrata<\/jats:italic>\n                      through stepwise exposure to increasing drug concentrations. Whole-genome sequencing revealed that nonsense mutations in the\n                      <jats:italic toggle=\"yes\">OSH2<\/jats:italic>\n                      gene (193C &gt; T and 3177C &gt; A) were key drivers of resistance. Functional validation in\n                      <jats:italic toggle=\"yes\">Candida albicans<\/jats:italic>\n                      confirmed that these\n                      <jats:italic toggle=\"yes\">OSH2<\/jats:italic>\n                      mutations conferred miltefosine resistance, demonstrating the conserved role of Osh2 across species. Multi-omics profiling of the\n                      <jats:italic toggle=\"yes\">osh2\u0394\/\u0394<\/jats:italic>\n                      mutant revealed significant upregulation of ergosterol biosynthesis genes, including\n                      <jats:italic toggle=\"yes\">ERG6<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ERG11<\/jats:italic>\n                      , and the accumulation of zymosterol, an intermediate in the ergosterol pathway. Chemogenetic dissection further elucidated the role of sterol metabolism in resistance:\n                      <jats:italic toggle=\"yes\">erg11\u0394\/\u0394<\/jats:italic>\n                      mutants, which are unable to synthesize zymosterol, exhibited hypersusceptibility to miltefosine, whereas\n                      <jats:italic toggle=\"yes\">erg6\u0394\/\u0394<\/jats:italic>\n                      strains, which accumulate zymosterol, showed innate resistance. Exogenous supplementation of zymosterol dose dependently increased the minimum inhibitory concentration of miltefosine in\n                      <jats:italic toggle=\"yes\">C. albicans<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">C. glabrata<\/jats:italic>\n                      , confirming that zymosterol accumulation is a key determinant of resistance. Our findings establish Osh2 as a critical regulator of membrane sterol flux and demonstrate that fungal lipid metabolic plasticity enables evasion of membrane-targeting antifungals. Therapeutic targeting of zymosterol biosynthesis enzymes may overcome such adaptive resistance mechanisms in invasive candidiasis, providing a new strategy to combat drug-resistant fungal infections.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00427-25","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T12:00:50Z","timestamp":1753272050000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Osh2 mediates\n                    <i>Candida<\/i>\n                    species resistance to miltefosine by regulating zymosterol accumulation"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8393-0259","authenticated-orcid":true,"given":"Yongqin","family":"Wu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04c4dkn09","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of 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