{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:25:05Z","timestamp":1792607105128,"version":"4.5.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T00:00:00Z","timestamp":1708473600000},"content-version":"vor","delay-in-days":55,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0108135j1003"],"award-info":[{"award-number":["JP22fk0108135j1003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23fk0108679j0201"],"award-info":[{"award-number":["JP23fk0108679j0201"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21fk0108428s0201"],"award-info":[{"award-number":["JP21fk0108428s0201"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21fk0108094"],"award-info":[{"award-number":["JP21fk0108094"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0108135j0003"],"award-info":[{"award-number":["JP22fk0108135j0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0108610j0002"],"award-info":[{"award-number":["JP22fk0108610j0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>In recent years, the incidence of invasive fungal infections has increased, resulting in considerable morbidity and mortality, particularly among immunocompromised individuals. Potential challenges in treating these infections with the few existing antifungal agents highlight the urgency of developing new ones. Here, we evaluated six alkyl polyamine compounds (APCs), not previously reported as antifungal drugs to our knowledge, that could deprive fungi of essential transition metals.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The APC with confirmed antifungal activity against Candida spp. was analysed by using transcriptomics, followed by metal-addition experiments, mass spectrometric analyses and intracellular zinc quantification with a fluorescent probe.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A cyclic APC with three pyridylmethyl groups, APC6, had high antifungal activity against a wide range of Candida species, including MDR Candida auris. We conclusively demonstrated that APC6 was able to capture zinc within fungal cells. APC6 not only exhibited activity against C. auris as a single agent but also enhanced the efficacy of an azole antifungal agent, voriconazole, in vitro and in vivo. APC6 disrupted the biofilms formed by Candida species.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This zinc-chelating compound has potential as an antifungal agent, and the control of zinc levels in Candida species could be a powerful approach to treating drug-resistant candidiasis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jacamr\/dlad155","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T11:15:51Z","timestamp":1708514151000},"source":"Crossref","is-referenced-by-count":8,"title":["A novel zinc-chelating compound has antifungal activity against a wide range of <i>Candida<\/i> species, including multidrug-resistant <i>Candida auris<\/i>"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8804-0645","authenticated-orcid":false,"given":"Takayuki","family":"Shinohara","sequence":"first","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases , Tokyo , Japan"},{"name":"Department of Infectious Diseases, The University of Tokyo Hospital , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Wada","sequence":"additional","affiliation":[{"name":"Center for Biosystems Dynamics Research, RIKEN , Kanagawa , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6355-716X","authenticated-orcid":false,"given":"Masahiro","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuko","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Nagi","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases , Tokyo , Japan"},{"name":"Antimicrobial Resistance Research Center, National Institute of Infectious Diseases , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8942-0869","authenticated-orcid":false,"given":"Yoshitsugu","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Fungal Infection, National Institute of Infectious Diseases , Tokyo , Japan"},{"name":"Leprosy Research Center, National Institute of Infectious Diseases , Tokyo , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,21]]},"reference":[{"key":"2024022909310853700_dlad155-B1","first-page":"11","article-title":"Emerging threats in antifungal-resistant fungal pathogens","volume":"3","author":"Sanglard","year":"2016","journal-title":"Front Med (Lausanne)"},{"key":"2024022909310853700_dlad155-B2","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1093\/cid\/ciy776","article-title":"Estimation of direct healthcare costs of fungal diseases in the United States","volume":"68","author":"Benedict","year":"2019","journal-title":"Clin Infect Dis"},{"key":"2024022909310853700_dlad155-B3","doi-asserted-by":"crossref","first-page":"R1520","DOI":"10.1016\/j.cub.2021.09.071","article-title":"Antifungal drug resistance: deciphering the mechanisms governing multidrug resistance in the fungal pathogen Candida glabrata","volume":"31","author":"Robbins","year":"2021","journal-title":"Curr Biol"},{"key":"2024022909310853700_dlad155-B4","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1021\/acs.chemrev.0c00199","article-title":"Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond","volume":"121","author":"Lee","year":"2021","journal-title":"Chem Rev"},{"key":"2024022909310853700_dlad155-B5","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1111\/myc.12781","article-title":"An outbreak due to Candida auris with prolonged colonisation and candidaemia in a tertiary care European hospital","volume":"61","author":"Ruiz-Gait\u00e1n","year":"2018","journal-title":"Mycoses"},{"key":"2024022909310853700_dlad155-B6","doi-asserted-by":"crossref","first-page":"e02529-18","DOI":"10.1128\/mBio.02529-18","article-title":"Genetic analysis of Candida auris implicates Hsp90 in morphogenesis and azole tolerance and Cdr1 in azole resistance","volume":"10","author":"Kim","year":"2019","journal-title":"mBio"},{"key":"2024022909310853700_dlad155-B7","doi-asserted-by":"crossref","first-page":"e01624-18","DOI":"10.1128\/JCM.01624-18","article-title":"Candida auris clinical isolates from South Korea: identification, antifungal susceptibility, and genotyping","volume":"57","author":"Kwon","year":"2019","journal-title":"J Clin Microbiol"},{"key":"2024022909310853700_dlad155-B8","doi-asserted-by":"crossref","first-page":"fux050","DOI":"10.1093\/femsre\/fux050","article-title":"Metals in fungal virulence","volume":"42","author":"Gerwien","year":"2018","journal-title":"FEMS Microbiol Rev"},{"key":"2024022909310853700_dlad155-B9","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.lab.2004.07.007","article-title":"Fungal susceptibility to zinc deprivation","volume":"144","author":"Lulloff","year":"2004","journal-title":"J Lab Clin Med"},{"key":"2024022909310853700_dlad155-B10","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/1348-0421.12596","article-title":"Association of the hypha-related protein Pra1 and zinc transporter Zrt1 with biofilm formation by the pathogenic yeast Candida albicans","volume":"62","author":"Kurakado","year":"2018","journal-title":"Microbiol Immunol"},{"key":"2024022909310853700_dlad155-B11","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1021\/ar900015x","article-title":"Metalloproteomes: a bioinformatic approach","volume":"42","author":"Andreini","year":"2009","journal-title":"Acc Chem Res"},{"key":"2024022909310853700_dlad155-B12","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1021\/pr0603699","article-title":"Zinc through the three domains of life","volume":"5","author":"Andreini","year":"2006","journal-title":"J Proteome Res"},{"key":"2024022909310853700_dlad155-B13","doi-asserted-by":"crossref","first-page":"179","DOI":"10.5941\/MYCO.2015.43.3.179","article-title":"The zinc transport systems and their regulation in pathogenic fungi","volume":"43","author":"Jung","year":"2015","journal-title":"Mycobiology"},{"key":"2024022909310853700_dlad155-B14","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/mmy\/myw013","article-title":"The ZIP family zinc transporters support the virulence of Cryptococcus neoformans","volume":"54","author":"Do","year":"2016","journal-title":"Med Mycol"},{"key":"2024022909310853700_dlad155-B15","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1093\/mmy\/myw045","article-title":"Hc zrt2, a zinc responsive gene, is indispensable for the survival of Histoplasma capsulatum in vivo","volume":"54","author":"Dade","year":"2016","journal-title":"Med Mycol"},{"key":"2024022909310853700_dlad155-B16","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1111\/cmi.12238","article-title":"The ZrfC alkaline zinc transporter is required for Aspergillus fumigatus virulence and its growth in the presence of the Zn\/Mn-chelating protein calprotectin","volume":"16","author":"Amich","year":"2014","journal-title":"Cell Microbiol"},{"key":"2024022909310853700_dlad155-B17","doi-asserted-by":"crossref","first-page":"e0195121","DOI":"10.1128\/spectrum.01951-21","article-title":"Selective metal chelation by a thiosemicarbazone derivative interferes with mitochondrial respiration and ribosome biogenesis in Candida albicans","volume":"10","author":"Duan","year":"2022","journal-title":"Microbiol Spectr"},{"key":"2024022909310853700_dlad155-B18","doi-asserted-by":"crossref","first-page":"e02024-17","DOI":"10.1128\/AAC.02024-17","article-title":"Novel zinc-attenuating compounds as potent broad-spectrum antifungal agents with in vitro and in vivo efficacy","volume":"62","author":"Cohrt","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"key":"2024022909310853700_dlad155-B19","doi-asserted-by":"crossref","first-page":"102208","DOI":"10.1016\/j.mib.2022.102208","article-title":"The molecular and genetic basis of antifungal resistance in the emerging fungal pathogen Candida auris","volume":"70","author":"Rybak","year":"2022","journal-title":"Curr Opin Microbiol"},{"key":"2024022909310853700_dlad155-B20","volume-title":"Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts\u2014Fourth Edition:M27","author":"CLSI","year":"2017"},{"key":"2024022909310853700_dlad155-B21","doi-asserted-by":"crossref","first-page":"1000133","DOI":"10.1371\/journal.pbio.1000133","article-title":"Biofilm matrix regulation by Candida albicans Zap1","volume":"7","author":"Nobile","year":"2009","journal-title":"PLoS Biol"},{"key":"2024022909310853700_dlad155-B22","doi-asserted-by":"crossref","first-page":"e1002076","DOI":"10.1371\/journal.pbio.1002076","article-title":"Activation and alliance of regulatory pathways in C. albicans during mammalian infection","volume":"13","author":"Xu","year":"2015","journal-title":"PLoS Biol"},{"key":"2024022909310853700_dlad155-B23","doi-asserted-by":"crossref","first-page":"36055","DOI":"10.1038\/srep36055","article-title":"Dual-species transcriptional profiling during systemic candidiasis reveals organ-specific host-pathogen interactions","volume":"6","author":"Hebecker","year":"2016","journal-title":"Sci Rep"},{"key":"2024022909310853700_dlad155-B24","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1002\/ejic.201700176","article-title":"1,4,7-Triazacyclononane-based bifunctional picolinate ligands for efficient copper complexation","volume":"18","author":"Guillou","year":"2017","journal-title":"Eur J Inorg Chem"},{"key":"2024022909310853700_dlad155-B25","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1246\/bcsj.38.771","article-title":"The stability constants of ethylenediaminetetraacetato, diaminetetraacetato and propylenediaminetetraacetato complexes of some divalent metal ions","volume":"38","author":"Ogino","year":"1965","journal-title":"Bull Chem Soc Jpn"},{"key":"2024022909310853700_dlad155-B26","doi-asserted-by":"crossref","first-page":"13039","DOI":"10.1073\/pnas.1511197112","article-title":"Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide","volume":"112","author":"Hein","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2024022909310853700_dlad155-B27","doi-asserted-by":"crossref","first-page":"17014","DOI":"10.1038\/s41598-017-17147-x","article-title":"Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity","volume":"7","author":"Sun","year":"2017","journal-title":"Sci Rep"},{"key":"2024022909310853700_dlad155-B28","doi-asserted-by":"crossref","first-page":"390","DOI":"10.3390\/microorganisms8030390","article-title":"Galleria mellonella for the evaluation of antifungal efficacy against medically important fungi, a narrative review","volume":"8","author":"Jemel","year":"2020","journal-title":"Microorganisms"},{"key":"2024022909310853700_dlad155-B29","doi-asserted-by":"crossref","first-page":"e00760-20","DOI":"10.1128\/mSphere.00760-20","article-title":"Comparative evaluations of the pathogenesis of Candida auris phenotypes and Candida albicans using clinically relevant murine models of infections","volume":"5","author":"Vila","year":"2020","journal-title":"mSphere"},{"key":"2024022909310853700_dlad155-B30","doi-asserted-by":"crossref","first-page":"e1002777","DOI":"10.1371\/journal.ppat.1002777","article-title":"Candida albicans scavenges host zinc via Pra1 during endothelial invasion","volume":"8","author":"Citiulo","year":"2012","journal-title":"PLoS Pathog"},{"key":"2024022909310853700_dlad155-B31","doi-asserted-by":"crossref","first-page":"2788","DOI":"10.3389\/fmicb.2019.02788","article-title":"Review on antifungal resistance mechanisms in the emerging pathogen Candida auris","volume":"10","author":"Chaabane","year":"2019","journal-title":"Front Microbiol"},{"key":"2024022909310853700_dlad155-B32","doi-asserted-by":"crossref","first-page":"e00578","DOI":"10.1002\/mbo3.578","article-title":"Candida auris: a systematic review and meta-analysis of current updates on an emerging multidrug-resistant pathogen","volume":"7","author":"Osei Sekyere","year":"2018","journal-title":"MicrobiologyOpen"},{"key":"2024022909310853700_dlad155-B33","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3390\/jof5030058","article-title":"On the origins of a species: what might explain the rise of Candida auris?","volume":"5","author":"Jackson","year":"2019","journal-title":"J Fungi"},{"key":"2024022909310853700_dlad155-B34","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1023\/A:1020603110255","article-title":"The role of intracellular zinc in modulation of life and death of Hep-2 cells","volume":"16","author":"Rudolf","year":"2003","journal-title":"Biometals"},{"key":"2024022909310853700_dlad155-B35","first-page":"190","article-title":"Ethambutol is toxic to retinal ganglion cells via an excitotoxic pathway","volume":"40","author":"Heng","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2024022909310853700_dlad155-B36","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1097\/00001756-200007140-00046","article-title":"Caspase inhibitors block zinc-chelator induced death of retinal ganglion cells","volume":"11","author":"Shindler","year":"2000","journal-title":"Neuroreport"},{"key":"2024022909310853700_dlad155-B37","first-page":"2391","article-title":"N-methyl-D-aspartate (NMDA)\u2013induced apoptosis in rat retina","volume":"40","author":"Lam","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2024022909310853700_dlad155-B38","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/1472-6882-12-213","article-title":"Some southern African plant species used to treat helminth infections in ethnoveterinary medicine have excellent antifungal activities","volume":"12","author":"Adamu","year":"2012","journal-title":"BMC Complement Altern Med"},{"key":"2024022909310853700_dlad155-B39","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.jep.2010.06.011","article-title":"Investigation of plant extracts in traditional medicine of the Brazilian Cerrado against protozoans and yeasts","volume":"131","author":"Albernaz","year":"2010","journal-title":"J Ethnopharmacol"},{"key":"2024022909310853700_dlad155-B40","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/lam.12086","article-title":"Hydroxyaldimines as potent in vitro anticryptococcal agents","volume":"57","author":"Magalh\u00e3es","year":"2013","journal-title":"Lett Appl Microbiol"},{"key":"2024022909310853700_dlad155-B41","doi-asserted-by":"crossref","first-page":"e01719-20","DOI":"10.1128\/AAC.01719-20","article-title":"The future of antifungal drug therapy: novel compounds and targets","volume":"65","author":"Mota Fernandes","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2024022909310853700_dlad155-B42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/BF02829935","article-title":"Zinc deficiency and its inherited disorders\u2014a review","volume":"1","author":"Leigh","year":"2006","journal-title":"Genes Nutr"},{"key":"2024022909310853700_dlad155-B43","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1128\/AAC.44.10.2693-2700.2000","article-title":"Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors","volume":"44","author":"Henry","year":"2000","journal-title":"Antimicrob Agents Chemother"}],"container-title":["JAC-Antimicrobial Resistance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/6\/1\/dlad155\/56755913\/dlad155.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/6\/1\/dlad155\/56755913\/dlad155.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T09:34:20Z","timestamp":1709199260000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jacamr\/article\/doi\/10.1093\/jacamr\/dlad155\/7611860"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,28]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,12,28]]}},"URL":"https:\/\/doi.org\/10.1093\/jacamr\/dlad155","relation":{},"ISSN":["2632-1823"],"issn-type":[{"value":"2632-1823","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,2]]},"published":{"date-parts":[[2023,12,28]]},"article-number":"dlad155"}}