{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T01:05:46Z","timestamp":1789088746412,"version":"build-2803163510"},"reference-count":19,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R21AI164578"],"award-info":[{"award-number":["R21AI164578"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["F32AI145160"],"award-info":[{"award-number":["F32AI145160"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"crossref","award":["R01AI52494"],"award-info":[{"award-number":["R01AI52494"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2023,10,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Multidrug resistance (MDR) transporters such as ATP-Binding Cassette (ABC) and Major Facilitator Superfamily proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity against\n            <jats:italic>Candida<\/jats:italic>\n            spp. compared to the fluphenazine and with activity against\n            <jats:italic>Candida<\/jats:italic>\n            spp. with reduced fluconazole susceptibility due to increased MDR transporters. Here, we show that the improved\n            <jats:italic>C. albicans<\/jats:italic>\n            activity is because fluphenazine induces its own resistance by triggering expression of\n            <jats:italic>Candida<\/jats:italic>\n            drug resistance (CDR) transporters while CWHM-974 induces expression but does not appear to be a substrate for the transporters or is insensitive to their effects through other mechanisms. We also found that fluphenazine and CWHM-974 are antagonistic with fluconazole in\n            <jats:italic>C. albicans<\/jats:italic>\n            but not in\n            <jats:italic>C. glabrata<\/jats:italic>\n            , despite inducing\n            <jats:italic>CDR1<\/jats:italic>\n            expression to high levels. Overall, CWHM-974 is one of the few examples of a molecule in which relatively small structural modifications significantly reduced susceptibility to multidrug transporter-mediated resistance.\n          <\/jats:p>","DOI":"10.1128\/aac.00567-23","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T13:02:50Z","timestamp":1694610170000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["CWHM-974 is a fluphenazine derivative with improved antifungal activity against\n            <i>Candida albicans<\/i>\n            due to reduced susceptibility to multidrug transporter-mediated resistance mechanisms"],"prefix":"10.1128","volume":"67","author":[{"given":"Aracely","family":"Miron-Ocampo","sequence":"first","affiliation":[{"name":"Microbiology\/Immunology, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah R.","family":"Beattie","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumitra","family":"Guin","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Saint Louis University , Saint Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Conway","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa , Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin J.","family":"Meyers","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Saint Louis University , Saint Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Scott","family":"Moye-Rowley","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, University of Iowa , Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6330-3365","authenticated-orcid":false,"given":"Damian J.","family":"Krysan","sequence":"additional","affiliation":[{"name":"Microbiology\/Immunology, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA"},{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa , Iowa City, Iowa, USA"},{"name":"Department of Molecular Physiology and Biophysics, University of Iowa , Iowa City, Iowa, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2011.01.001"},{"key":"e_1_3_3_3_2","first-page":"459","article-title":"Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases","volume":"9","author":"Xu F","year":"2019","unstructured":"Xu F , Xia Y , Feng Z , Lin W , Xue Q , Jiang J , Yu X , Peng C , Luo M , Yang Y , Wei Y , Yu L . 2019. Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases. Am J Cancer Res 9:459\u2013478.","journal-title":"Am J Cancer Res"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.31.5.834"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.7b00157"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.3.6.1639-1652.2004"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01342-17"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00078-19"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12327"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.7.2785-2792.2005"},{"key":"e_1_3_3_11_2","first-page":"509","article-title":"Inhibition of calmodulin by phenothiazines and related drugs: structure-activity relationships","volume":"222","author":"Prozialeck WC","year":"1982","unstructured":"Prozialeck WC , Weiss B . 1982. Inhibition of calmodulin by phenothiazines and related drugs: structure-activity relationships. J Pharmacol Exp Ther 222:509\u2013516.","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.8.1968"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-019-09960-3"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0924-8579(03)00214-0"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-019-0322-2"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-143-2-405"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009005"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000783"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.19"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00934-19"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00567-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.00567-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T13:03:35Z","timestamp":1697634215000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.00567-23"}},"subtitle":[],"editor":[{"given":"Andreas H.","family":"Groll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,10,18]]},"references-count":19,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10,18]]}},"alternative-id":["10.1128\/aac.00567-23"],"URL":"https:\/\/doi.org\/10.1128\/aac.00567-23","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,18]]},"assertion":[{"value":"2023-05-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00567-23"}}