{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:48:44Z","timestamp":1790628524559,"version":"4.1.0"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2012,3,1]],"date-time":"2012-03-01T00:00:00Z","timestamp":1330560000000},"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":["Eukaryot Cell"],"published-print":{"date-parts":[[2012,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The zygomycete\n            <jats:named-content content-type=\"genus-species\">Mucor circinelloides<\/jats:named-content>\n            is an opportunistic fungal pathogen that commonly infects patients with malignancies, diabetes mellitus, and solid organ transplants. Despite the widespread use of antifungal therapy in the management of zygomycosis, the incidence of infections continues to rise among immunocompromised individuals. In this study, we established that the target and mechanism of antifungal action of the immunosuppressant rapamycin in\n            <jats:named-content content-type=\"genus-species\">M. circinelloides<\/jats:named-content>\n            are mediated via conserved complexes with FKBP12 and a Tor homolog. We found that spontaneous mutations that disrupted conserved residues in FKBP12 conferred rapamycin and FK506 resistance. Disruption of the FKBP12-encoding gene,\n            <jats:italic>fkbA<\/jats:italic>\n            , also conferred rapamycin and FK506 resistance. Expression of\n            <jats:named-content content-type=\"genus-species\">M. circinelloides<\/jats:named-content>\n            FKBP12 (\n            <jats:italic>Mc<\/jats:italic>\n            FKBP12) complemented a\n            <jats:named-content content-type=\"genus-species\">Saccharomyces cerevisiae<\/jats:named-content>\n            mutant strain lacking FKBP12 to restore rapamycin sensitivity. Expression of the\n            <jats:italic>Mc<\/jats:italic>\n            Tor FKBP12-rapamycin binding (FRB) domain conferred rapamycin resistance in\n            <jats:named-content content-type=\"genus-species\">S. cerevisiae<\/jats:named-content>\n            , and\n            <jats:italic>Mc<\/jats:italic>\n            FKBP12 interacted in a rapamycin-dependent fashion with the\n            <jats:italic>Mc<\/jats:italic>\n            Tor FRB domain in a yeast two-hybrid assay, validating\n            <jats:italic>Mc<\/jats:italic>\n            FKBP12 and\n            <jats:italic>Mc<\/jats:italic>\n            Tor as conserved targets of rapamycin. We showed that\n            <jats:italic>in vitro<\/jats:italic>\n            , rapamycin exhibited potent growth inhibitory activity against\n            <jats:named-content content-type=\"genus-species\">M. circinelloides<\/jats:named-content>\n            . In a\n            <jats:named-content content-type=\"genus-species\">Galleria mellonella<\/jats:named-content>\n            model of systemic mucormycosis, rapamycin improved survival by 50%, suggesting that rapamycin and nonimmunosuppressive analogs have the potential to be developed as novel antifungal therapies for treatment of patients with mucormycosis.\n          <\/jats:p>","DOI":"10.1128\/ec.05284-11","type":"journal-article","created":{"date-parts":[[2011,12,31]],"date-time":"2011-12-31T03:28:54Z","timestamp":1325302134000},"page":"270-281","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":85,"title":["Rapamycin Exerts Antifungal Activity\n            <i>In Vitro<\/i>\n            and\n            <i>In Vivo<\/i>\n            against Mucor circinelloides via FKBP12-Dependent Inhibition of Tor"],"prefix":"10.1128","volume":"11","author":[{"given":"Robert J.","family":"Bastidas","sequence":"first","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecelia A.","family":"Shertz","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Chan","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"},{"name":"Medicine, Duke University Medical Center, Durham, North Carolina, USA"},{"name":"Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria E.","family":"Cardenas","sequence":"additional","affiliation":[{"name":"Departments of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.31.539"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802668105"},{"key":"e_1_3_3_4_2","first-page":"856","article-title":"Signaling cascades as drug targets in model and pathogenic fungi","volume":"9","author":"Bastidas RJ","year":"2008","unstructured":"BastidasRJ ReedyJL Morales-JohanssonH HeitmanJ CardenasME. 2008. 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