{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T12:15:59Z","timestamp":1780575359124,"version":"3.54.1"},"reference-count":44,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2018,4,26]],"date-time":"2018-04-26T00:00:00Z","timestamp":1524700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Wellcome Trust Research Councils, UK","award":["100480\/Z\/12"],"award-info":[{"award-number":["100480\/Z\/12"]}]},{"name":"Wellcome Trust Research Councils, UK","award":["100480\/Z\/12"],"award-info":[{"award-number":["100480\/Z\/12"]}]},{"name":"Novo Seeds, Denmark"},{"name":"Boehringer Ingelheim Venture Fund, Germany"},{"name":"Spanish Ministry of Economy and Competitiveness","award":["SAF2013-48382-R"],"award-info":[{"award-number":["SAF2013-48382-R"]}]},{"DOI":"10.13039\/100012774","name":"Innovation Fund, Denmark","doi-asserted-by":"crossref","award":["4019-00019B"],"award-info":[{"award-number":["4019-00019B"]}],"id":[{"id":"10.13039\/100012774","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":[[2018,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            An increase in the incidence of rare but hard-to-treat invasive fungal pathogens as well as resistance to the currently available antifungal drugs calls for new broad-spectrum antifungals with a novel mechanism of action. Here we report the identification and characterization of two novel zinc-attenuating compounds, ZAC307 and ZAC989, which exhibit broad-spectrum\n            <jats:italic>in vitro<\/jats:italic>\n            antifungal activity and\n            <jats:italic>in vivo<\/jats:italic>\n            efficacy in a fungal kidney burden candidiasis model. The compounds were identified serendipitously as part of a drug discovery process aimed at finding novel inhibitors of the fungal plasma membrane proton ATPase Pma1. Based on their structure, we hypothesized that they might act as zinc chelators. Indeed, both fluorescence-based affinity determination and potentiometric assays revealed these compounds, subsequently termed zinc-attenuating compounds (ZACs), to have strong affinity for zinc, and their growth inhibitory effects on\n            <jats:named-content content-type=\"genus-species\">Candida albicans<\/jats:named-content>\n            and\n            <jats:named-content content-type=\"genus-species\">Aspergillus fumigatus<\/jats:named-content>\n            could be inactivated by the addition of exogenous zinc to fungal growth media. We determined the ZACs to be fungistatic, with a low propensity for resistance development. Gene expression analysis suggested that the ZACs interfere negatively with the expression of genes encoding the major components of the\n            <jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>\n            zinc uptake system, thus supporting perturbance of zinc homeostasis as the likely mode of action. With demonstrated\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            antifungal activity, low propensity for resistance development, and a novel mode of action, the ZACs represent a promising new class of antifungal compounds, and their advancement in a drug development program is therefore warranted.\n          <\/jats:p>","DOI":"10.1128\/aac.02024-17","type":"journal-article","created":{"date-parts":[[2018,2,13]],"date-time":"2018-02-13T11:33:25Z","timestamp":1518521605000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with\n            <i>In Vitro<\/i>\n            and\n            <i>In Vivo<\/i>\n            Efficacy"],"prefix":"10.1128","volume":"62","author":[{"given":"Karen A. O'Hanlon","family":"Cohrt","sequence":"first","affiliation":[{"name":"Pcovery, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mar\u00edn","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Funcional y Gen\u00f3mica, Consejo Superior de Investigaciones Cient\u00edficas, Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7855-3567","authenticated-orcid":false,"given":"Lasse","family":"Kjellerup","sequence":"additional","affiliation":[{"name":"Pcovery, Copenhagen, Denmark"},{"name":"Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes D.","family":"Clausen","sequence":"additional","affiliation":[{"name":"Pcovery, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Dalby-Brown","sequence":"additional","affiliation":[{"name":"Pcovery, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Antonio","family":"Calera","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Funcional y Gen\u00f3mica, Departamento de Microbiolog\u00eda y Gen\u00e9tica, Universidad de Salamanca, Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5776-0989","authenticated-orcid":false,"given":"Anne-Marie Lund","family":"Winther","sequence":"additional","affiliation":[{"name":"Pcovery, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2836"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201540558"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12238"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000639"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2011.01.021"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsyr\/fov071"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00080"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2012.00028"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1152449"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lab.2004.07.007"},{"key":"e_1_3_2_12_2","first-page":"187","article-title":"Culture conditions for zinc- and pH-regulated gene expression studies in Aspergillus fumigatus","volume":"10","author":"Moreno MA","year":"2007","unstructured":"Moreno MA, Amich J, Vicentefranqueira R, Leal F, Calera JA. 2007. 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Cancer Res 48:4827\u20134833.","journal-title":"Cancer Res"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-539-8_35"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02024-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02024-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T21:11:48Z","timestamp":1645477908000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02024-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,5]]}},"alternative-id":["10.1128\/AAC.02024-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.02024-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5]]},"assertion":[{"value":"2017-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-02-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02024-17"}}