{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:16:38Z","timestamp":1789514198932,"version":"build-2803163510"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["SRG\/2019\/000514"],"award-info":[{"award-number":["SRG\/2019\/000514"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["SRG\/2019\/000514"],"award-info":[{"award-number":["SRG\/2019\/000514"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010803","name":"Department of Biotechnology","doi-asserted-by":"publisher","award":["BT\/PR32349\/MED\/29\/1456\/2019"],"award-info":[{"award-number":["BT\/PR32349\/MED\/29\/1456\/2019"]}],"id":[{"id":"10.13039\/501100010803","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010803","name":"Department of Biotechnology","doi-asserted-by":"publisher","award":["BT\/INF\/22\/SP45072\/2022"],"award-info":[{"award-number":["BT\/INF\/22\/SP45072\/2022"]}],"id":[{"id":"10.13039\/501100010803","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004410","name":"EMBO","doi-asserted-by":"publisher","award":["SEG-9787"],"award-info":[{"award-number":["SEG-9787"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>PTR transporters mediate the uptake of dipeptides\/tripeptides as well as peptidomimetic drugs across diverse organisms, including bacteria, yeast, and humans. Our previous study identified three PTR transporters in Candida auris, with Ptr_C serving as a key player in the uptake of peptide substrates, including the antifungal, l-norvalyl-N3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (Nva-FMDP). This study aims to evaluate the efficacy of different FMDP-based antifungal variants against C. auris, investigate the contribution of Ptr_C in their uptake, and establish a heterologous system to screen for peptide-based inhibitors that exploit Ptr_C for cellular entry.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>In this study, utilizing deletion mutants of C. auris PTR transporters, we demonstrate that Ptr_C is the primary transporter facilitating the uptake of FMDP-based antifungal peptides. Furthermore, we developed a Ptr_C overexpression system in Saccharomyces cerevisiae, enabling rapid identification of antifungal peptides capable of exploiting this transporter using simplistic growth-based assays. The system\u2019s competence was further validated by constructing a few key site-directed mutants that alter the functional specificity of Ptr_C.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jambio\/lxaf170","type":"journal-article","created":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T07:48:41Z","timestamp":1751701721000},"source":"Crossref","is-referenced-by-count":3,"title":["The proton-dependent oligopeptide transporter Ptr_C serves as an efficient system for antifungal delivery into <i>Candida auris<\/i>"],"prefix":"10.1093","volume":"136","author":[{"given":"Rosy","family":"Khatoon","sequence":"first","affiliation":[{"name":"Amity Institute of Biotechnology, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Skwarecki","sequence":"additional","affiliation":[{"name":"Gda\u0144sk University of Technology Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, , 11\/12 Narutowicza St., 80-233, Gda\u0144sk ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryszard","family":"Andruszkiewicz","sequence":"additional","affiliation":[{"name":"Gda\u0144sk University of Technology Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, , 11\/12 Narutowicza St., 80-233, Gda\u0144sk ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amandeep","family":"Saini","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarita","family":"Malik","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajendra","family":"Prasad","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]},{"name":"Amity Institute of Integrative Sciences and Health, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amresh","family":"Prakash","sequence":"additional","affiliation":[{"name":"Amity Institute of Integrative Sciences and Health, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u0142awomir","family":"Milewski","sequence":"additional","affiliation":[{"name":"Gda\u0144sk University of Technology Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, , 11\/12 Narutowicza St., 80-233, Gda\u0144sk ,","place":["Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9319-4593","authenticated-orcid":false,"given":"Atanu","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]},{"name":"Amity Institute of Integrative Sciences and Health, Amity University Haryana , Amity Education Valley, Panchgaon, Manesar, Gurugram, Haryana 122413 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"2025071713014017300_bib1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"2025071713014017300_bib2","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.chembiol.2020.03.001","article-title":"New spins on old drugs: enhancing activity of antifungals","volume":"27","author":"Alspaugh","year":"2020","journal-title":"Cell Chem Biol"},{"key":"2025071713014017300_bib3","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.1021\/jm00393a005","article-title":"Synthesis and biological properties of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid dipeptides, a novel group of antimicrobial agents","volume":"30","author":"Andruszkiewicz","year":"1987","journal-title":"J Med Chem"},{"key":"2025071713014017300_bib4","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1021\/jm00163a022","article-title":"Anticandidal properties of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid oligopeptides","volume":"33","author":"Andruszkiewicz","year":"1990","journal-title":"J Med Chem"},{"key":"2025071713014017300_bib5","doi-asserted-by":"publisher","first-page":"e1000544","DOI":"10.1371\/journal.pcbi.1000544","article-title":"Perturbation-response scanning reveals ligand entry-exit mechanisms of ferric binding protein","volume":"5","author":"Atilgan","year":"2009","journal-title":"PLoS Comput Biol"},{"key":"2025071713014017300_bib6","doi-asserted-by":"publisher","first-page":"W35","DOI":"10.1093\/nar\/gkq415","article-title":"Multi-harmony: detecting functional specificity from sequence alignment","volume":"38","author":"Brandt","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2025071713014017300_bib7","doi-asserted-by":"publisher","first-page":"e02123","DOI":"10.1128\/mBio.02123-20","article-title":"Antimicrobial peptides: a new frontier in antifungal therapy","volume":"11","author":"Buda\u00a0De\u00a0Cesare","year":"2020","journal-title":"mBio"},{"key":"2025071713014017300_bib8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1080\/21505594.2016.1216283","article-title":"Antifungal adjuvants: preserving and extending the antifungal arsenal","volume":"8","author":"Butts","year":"2017","journal-title":"Virulence"},{"key":"2025071713014017300_bib9","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1128\/EC.00008-13","article-title":"Roles of different peptide transporters in nutrient acquisition in Candida albicans","volume":"12","author":"Dunkel","year":"2013","journal-title":"Euk Cell"},{"key":"2025071713014017300_bib10","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1016\/j.str.2015.07.002","article-title":"Cooperative dynamics of intact AMPA and NMDA glutamate receptors: similarities and subfamily-specific differences","volume":"23","author":"Dutta","year":"2015","journal-title":"Structure"},{"key":"2025071713014017300_bib11","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1093\/bioinformatics\/btl448","article-title":"Anisotropic network model: systematic evaluation and a new web interface","volume":"22","author":"Eyal","year":"2006","journal-title":"Bioinformatics"},{"key":"2025071713014017300_bib12","doi-asserted-by":"publisher","first-page":"100903","DOI":"10.1016\/S2666-5247(24)00135-6","article-title":"the diverse genomes of Candida auris","volume":"5","author":"Gifford","year":"2024","journal-title":"Lancet Microbe"},{"key":"2025071713014017300_bib13","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1093\/jac\/dky153","article-title":"Evaluation of the efficacy of rezafungin, a novel echinocandin, in the treatment of disseminated Candida auris infection using an immunocompromised mouse model","volume":"73","author":"Hager","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2025071713014017300_bib14","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1080\/09687680010029374","article-title":"Multiplicity and regulation of genes encoding peptide transporters in Saccharomyces cerevisiae","volume":"18","author":"Hauser","year":"2001","journal-title":"Mol Membr Biol"},{"key":"2025071713014017300_bib15","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1128\/AAC.05706-11","article-title":"The monoamine oxidase a inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates","volume":"56","author":"Holmes","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms3502","article-title":"Analysing the substrate multispecificity of a proton-coupled oligopeptide transporter using a dipeptide library","volume":"4","author":"Ito","year":"2013","journal-title":"Nat Commun"},{"key":"2025071713014017300_bib17","doi-asserted-by":"publisher","first-page":"e0005322","DOI":"10.1128\/aac.00053-22","article-title":"Candida auris pan-drug-resistant to four classes of antifungal agents","volume":"66","author":"Jacobs","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib18","doi-asserted-by":"publisher","first-page":"4223","DOI":"10.1007\/s00253-022-11998-9","article-title":"Genome-wide analysis of PTR transporters in Candida species and their functional characterization in Candida auris","volume":"106","author":"Khatoon","year":"2022","journal-title":"Appl Microbiol Biotechnol"},{"key":"2025071713014017300_bib19","doi-asserted-by":"publisher","first-page":"7085","DOI":"10.1007\/s00253-022-12189-2","article-title":"Genomic landscape of the DHA1 family in Candida auris and mapping substrate repertoire of CauMdr1","volume":"106","author":"Khatoon","year":"2022","journal-title":"Appl Microbiol Biotechnol"},{"key":"2025071713014017300_bib20","doi-asserted-by":"publisher","first-page":"783","DOI":"10.3389\/fmicb.2015.00783","article-title":"Chemosensitization of multidrug resistant Candida albicans by the oxathiolone fused chalcone derivatives","volume":"6","author":"\u0141a\u0327cka","year":"2015","journal-title":"Front Microbiol"},{"key":"2025071713014017300_bib21","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1128\/EC.00091-07","article-title":"Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae","volume":"6","author":"Lamping","year":"2007","journal-title":"Euk Cell"},{"key":"2025071713014017300_bib22","doi-asserted-by":"publisher","first-page":"261","DOI":"10.3390\/jof6040261","article-title":"Nikkomycin Z\u2014Ready to meet the promise?","volume":"6","author":"Larwood","year":"2020","journal-title":"J Fungi"},{"key":"2025071713014017300_bib23","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1128\/AAC.10.3.483","article-title":"Basis for the design of anticandidal agents from studies of peptide utilization in Candida albicans","volume":"10","author":"Lichliter","year":"1976","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib24","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1128\/AAC.35.1.36","article-title":"Mechanism of action of anticandidal dipeptides containing inhibitors of glucosamine-6-phosphate synthase","volume":"35","author":"Milewski","year":"1991","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib25","doi-asserted-by":"publisher","first-page":"e482","DOI":"10.1016\/S2666-5247(23)00114-3","article-title":"Candida auris: an emerging antimicrobial-resistant organism with the highest level of concern","volume":"4","author":"Mishra","year":"2023","journal-title":"Lancet Microbe"},{"key":"2025071713014017300_bib26","doi-asserted-by":"publisher","first-page":"6","DOI":"10.15585\/mmwr.mm6901a2","article-title":"Candida auris isolates resistant to three classes of antifungal medications\u2014New York, 2019","volume":"69","author":"Ostrowsky","year":"2020","journal-title":"Morb Mortal Wkly Rep"},{"key":"2025071713014017300_bib27","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.ejmech.2014.12.007","article-title":"Synthesis, anticandidal activity of N(3)-(4-methoxyfumaroyl)-(S)-2,3-diaminopropanoic amide derivatives\u2014novel inhibitors of glucosamine-6-phosphate synthase","volume":"90","author":"Pawlak","year":"2015","journal-title":"Eur J Med Chem"},{"key":"2025071713014017300_bib28","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci"},{"key":"2025071713014017300_bib29","doi-asserted-by":"publisher","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":"2025071713014017300_bib30","doi-asserted-by":"publisher","first-page":"2154","DOI":"10.3389\/fmicb.2017.02154","article-title":"Transport deficiency is the molecular basis of Candida albicans resistance to antifungal oligopeptides","volume":"8","author":"Schielmann","year":"2017","journal-title":"Front Microbiol"},{"key":"2025071713014017300_bib31","doi-asserted-by":"publisher","first-page":"e3060","DOI":"10.1002\/psc.3060","article-title":"Antifungal dipeptides incorporating an inhibitor of homoserine dehydrogenase","volume":"24","author":"Skwarecki","year":"2018","journal-title":"J Pept Sci"},{"key":"2025071713014017300_bib32","doi-asserted-by":"publisher","first-page":"100878","DOI":"10.1016\/S2666-5247(24)00101-0","article-title":"Detection and characterisation of a sixth Candida auris clade in Singapore: a genomic and phenotypic study","volume":"5","author":"Suphavilai","year":"2024","journal-title":"Lancet Microbe"},{"key":"2025071713014017300_bib33","doi-asserted-by":"publisher","first-page":"4056","DOI":"10.1016\/j.apsb.2022.08.001","article-title":"Small molecules for combating multidrug-resistant superbug Candida auris infections","volume":"12","author":"Tu","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"2025071713014017300_bib34","doi-asserted-by":"publisher","first-page":"e0141922","DOI":"10.1128\/aac.01419-22","article-title":"Clinical efficacy and safety of a novel antifungal, fosmanogepix, in patients with Candidemia caused by Candida auris: results from a phase 2 trial","volume":"67","author":"Vazquez","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib35","doi-asserted-by":"publisher","first-page":"4057","DOI":"10.1128\/AAC.01648-07","article-title":"Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multidrug efflux pumps","volume":"52","author":"Wakiec","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib36","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.3389\/fmicb.2019.01445","article-title":"ABC transporter genes show upregulated expression in drug-resistant clinical isolates of Candida auris: a genome-wide characterization of ATP-binding cassette (ABC) transporter genes","volume":"10","author":"Wasi","year":"2019","journal-title":"Front Microbiol"},{"key":"2025071713014017300_bib37","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","article-title":"Jalview Version 2\u2014a multiple sequence alignment editor and analysis workbench","volume":"25","author":"Waterhouse","year":"2009","journal-title":"Bioinformatics"},{"key":"2025071713014017300_bib38","doi-asserted-by":"publisher","first-page":"e02694","DOI":"10.1128\/AAC.02694-20","article-title":"Ibrexafungerp demonstrates in vitro activity against fluconazole-resistant Candida auris and in vivo efficacy with delayed initiation of therapy in an experimental model of invasive Candidiasis","volume":"65","author":"Wiederhold","year":"2021","journal-title":"Antimicrob Agents Chemother"},{"key":"2025071713014017300_bib39","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1128\/jb.160.3.884-888.1984","article-title":"Sensitivity to nikkomycin Z in Candida albicans: role of peptide permeases","volume":"160","author":"Yadan","year":"1984","journal-title":"J Bacteriol"},{"key":"2025071713014017300_bib40","doi-asserted-by":"publisher","first-page":"3657","DOI":"10.1093\/bioinformatics\/btab187","article-title":"ProDy 2.0: increased scale and scope after 10 years of protein dynamics modelling with Python","volume":"37","author":"Zhang","year":"2021","journal-title":"Bioinformatics"}],"container-title":["Journal of Applied Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jambio\/advance-article-pdf\/doi\/10.1093\/jambio\/lxaf170\/63692922\/lxaf170.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jambio\/article-pdf\/136\/7\/lxaf170\/63692922\/lxaf170.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jambio\/article-pdf\/136\/7\/lxaf170\/63692922\/lxaf170.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T17:01:54Z","timestamp":1752771714000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jambio\/article\/doi\/10.1093\/jambio\/lxaf170\/8191242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":40,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jambio\/lxaf170","relation":{},"ISSN":["1365-2672"],"issn-type":[{"value":"1365-2672","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,7]]},"published":{"date-parts":[[2025,7,1]]},"article-number":"lxaf170"}}