{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T09:09:16Z","timestamp":1764493756327},"reference-count":44,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2013,9,1]],"date-time":"2013-09-01T00:00:00Z","timestamp":1377993600000},"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":[[2013,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant\n            <jats:named-content content-type=\"genus-species\">Mucorales<\/jats:named-content>\n            . We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37\u00b0C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            , phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome\n            <jats:italic>c<\/jats:italic>\n            release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 \u03bcg\/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 \u03bcg\/ml) for\n            <jats:named-content content-type=\"genus-species\">Rhizopus oryzae<\/jats:named-content>\n            ,\n            <jats:named-content content-type=\"genus-species\">Cunninghamella bertholletiae<\/jats:named-content>\n            , and\n            <jats:italic>Mucor circinelloides<\/jats:italic>\n            . Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of\n            <jats:italic>R. oryzae<\/jats:italic>\n            (10 to 50%),\n            <jats:named-content content-type=\"genus-species\">C. bertholletiae<\/jats:named-content>\n            (5 to 50%), and\n            <jats:named-content content-type=\"genus-species\">M. circinelloides<\/jats:named-content>\n            (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders\n            <jats:named-content content-type=\"genus-species\">Mucorales<\/jats:named-content>\n            sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.\n          <\/jats:p>","DOI":"10.1128\/ec.00138-13","type":"journal-article","created":{"date-parts":[[2013,7,13]],"date-time":"2013-07-13T01:27:53Z","timestamp":1373678873000},"page":"1225-1234","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["The Calcineurin Pathway Inhibitor Tacrolimus Enhances the\n            <i>In Vitro<\/i>\n            Activity of Azoles against Mucorales via Apoptosis"],"prefix":"10.1128","volume":"12","author":[{"given":"F.","family":"Shirazi","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. P.","family":"Kontoyiannis","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Infection Control and Employee Health, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Principles and practice of infectious diseases","author":"Kontoyiannis DP","unstructured":"KontoyiannisDPLewisRE. Agents for the treatment of mucormycosis. In MandellGLBennettJEDolinR (ed), Principles and practice of infectious diseases, in press . 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