{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:41:07Z","timestamp":1792510867955,"version":"4.5.0"},"reference-count":15,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP26fk0108700"],"award-info":[{"award-number":["JP26fk0108700"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K11656"],"award-info":[{"award-number":["24K11656"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013236","name":"MSD Life Science Foundation, Public Interest Incorporated Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013236","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Fosmanogepix (FMGX) is the prodrug of manogepix (MGX), which targets Gwt1, an inositol acyltransferase encoded by\n                      <jats:italic toggle=\"yes\">GWT1<\/jats:italic>\n                      and required for glycosylphosphatidylinositol anchor biosynthesis. To identify genetic changes associated with reduced MGX susceptibility in\n                      <jats:italic toggle=\"yes\">Candida auris<\/jats:italic>\n                      , we exposed strain NCPF8971 to MGX. A stable isolate with an MGX minimum inhibitory concentration (MIC) of 1.0 \u00b5g\/mL compared with 0.03 \u00b5g\/mL for the parental strain carried\n                      <jats:italic toggle=\"yes\">GWT1<\/jats:italic>\n                      A397T and\n                      <jats:italic toggle=\"yes\">TAC1B<\/jats:italic>\n                      F214I substitutions. Reciprocal CRISPR-Cas9 editing demonstrated that\n                      <jats:italic toggle=\"yes\">GWT1<\/jats:italic>\n                      A397T,\n                      <jats:italic toggle=\"yes\">TAC1B<\/jats:italic>\n                      F214I, and the combined substitutions increased the MIC to 0.06, 0.5, and 1.0 \u00b5g\/mL, respectively; reversion restored the MIC stepwise to the parental level. In a\n                      <jats:italic toggle=\"yes\">Galleria mellonella<\/jats:italic>\n                      infection model, FMGX improved survival and reduced fungal burden in larvae infected with the parental strain, whereas these effects were attenuated or absent in larvae infected with the engineered mutants. These findings identify\n                      <jats:italic toggle=\"yes\">GWT1<\/jats:italic>\n                      A397T as a modest contributor to reduced MGX susceptibility and show that this target alteration further increases the MIC in a\n                      <jats:italic toggle=\"yes\">TAC1B<\/jats:italic>\n                      F214I background. The combined genotype was associated with a diminished FMGX treatment response in this invertebrate model.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        <jats:italic toggle=\"yes\">Candida auris<\/jats:italic>\n                        is an emerging yeast that can resist several antifungal drugs and cause difficult-to-treat invasive infections. Fosmanogepix is an antifungal agent that acts on a target different from those of existing drugs. We investigated how\n                        <jats:italic toggle=\"yes\">C. auris<\/jats:italic>\n                        could become less susceptible to fosmanogepix and whether the responsible genetic changes would affect treatment in an infection model. We found that a change in the protein targeted by the drug modestly reduced susceptibility, whereas a change in a regulatory protein previously linked to increased activity of a drug efflux pump caused a greater reduction; the combination of both changes further weakened the drug\u2019s activity. The combined changes were also associated with a reduced response to fosmanogepix in an insect infection model. These findings show that changes affecting the drug target and drug efflux may act together to reduce antifungal activity and support monitoring for multiple pathways of reduced susceptibility.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02078-26","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:02:17Z","timestamp":1788267737000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["A novel\n                    <i>GWT1<\/i>\n                    A397T substitution combined with\n                    <i>TAC1B<\/i>\n                    F214I reduces manogepix susceptibility and fosmanogepix efficacy in\n                    <i>Candida auris<\/i>"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8554-3482","authenticated-orcid":true,"given":"Tatsuro","family":"Hirayama","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/058h74p94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences","place":["Nagasaki, Japan"]},{"id":[{"id":"https:\/\/ror.org\/058h74p94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences","place":["Nagasaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsume","family":"Kitahori","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/058h74p94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences","place":["Nagasaki, 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