{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:16:41Z","timestamp":1789514201117,"version":"build-2803163510"},"reference-count":26,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T00:00:00Z","timestamp":1631059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO-2020\/39\/B\/ST4\/01509"],"award-info":[{"award-number":["UMO-2020\/39\/B\/ST4\/01509"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A molecular umbrella composed of two O-sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a \u201ctrimethyl lock\u201d (TML) or o-dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates demonstrated antifungal in vitro activity against C. albicans and C. glabrata but not against C. krusei, with MIC90 values in the 0.22\u20130.99 mM range and were not hemolytic. Antifungal activity of the most active conjugate 24c, containing the TML\u2013pimelate linker, was comparable to that of intact cispentacin. A structural analogue of 24c, containing the Nap-NH2 fluorescent probe, was accumulated in Candida cells, and TML-containing conjugates were cleaved in cell-free extract of C. albicans cells. These results suggest that a molecular umbrella can be successfully applied as a nanocarrier for the construction of cleavable antifungal conjugates.<\/jats:p>","DOI":"10.3390\/molecules26185475","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T21:28:45Z","timestamp":1631136525000},"page":"5475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular Umbrella as a Nanocarrier for Antifungals"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7070-6071","authenticated-orcid":false,"given":"Andrzej S.","family":"Skwarecki","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Technology and Biochemistry and BioTechMed Centre, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Martynow","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biochemistry and BioTechMed Centre, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-0881","authenticated-orcid":false,"given":"Maria J.","family":"Milewska","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and BioTechMed Centre, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2616-4495","authenticated-orcid":false,"given":"S\u0142awomir","family":"Milewski","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biochemistry and BioTechMed Centre, Gda\u0144sk University of Technology, 80-233 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/cc13948","article-title":"The future of antibiotics","volume":"18","author":"Spellberg","year":"2014","journal-title":"Crit. Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/S1473-3099(18)30648-0","article-title":"Public health burden of antimicrobial resistance in Europe","volume":"19","author":"Tacconelli","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R., and Denning, D. (2017). Global and multi-national prevalence of fungal diseases destimate precision. J. Fungi, 3.","DOI":"10.3390\/jof3040057"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1126\/science.aap7999","article-title":"Worldwide emergence of resistance to antifungal drugs challenges human health and food security","volume":"360","author":"Fisher","year":"2018","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/S0140-6736(05)67381-3","article-title":"Advances and challenges in management of invasive mycoses","volume":"366","author":"Patterson","year":"2005","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3389\/fmed.2016.00011","article-title":"Emerging threats in antifungal-resistant fungal pathogens","volume":"3","author":"Sanglard","year":"2016","journal-title":"Front. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jconrel.2011.07.002","article-title":"\u201cNanoantibiotics\u201d: A new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era","volume":"156","author":"Huh","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1002\/med.21588","article-title":"Drug delivery systems designed to overcome antimicrobial resistance","volume":"39","author":"Pham","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1021\/bc800296g","article-title":"Bioconjugate-based molecular umbrellas","volume":"20","author":"Janout","year":"2009","journal-title":"Bioconjug. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1021\/bc9003074","article-title":"Cellular uptake mechanism of molecular umbrella","volume":"20","author":"Ge","year":"2009","journal-title":"Bioconjug. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1021\/ja000007g","article-title":"Molecular umbrella-assisted transport of a hydrophilic peptide across a phospholipid membrane","volume":"122","author":"Janout","year":"2000","journal-title":"J. Am. Chem. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.1021\/ja010124r","article-title":"Molecular umbrella-assisted transport of glutathione across a phospholipid membrane","volume":"123","author":"Janout","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1021\/acs.bioconjchem.5b00463","article-title":"Taming amphotericin B","volume":"26","author":"Janout","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Regen, S.L. (2021). Improving the cellular selectivity of a membrane-disrupting antimicrobial agent by monomer control and by taming. Molecules, 26.","DOI":"10.3390\/molecules26020374"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1021\/acs.bioconjchem.8b00136","article-title":"Molecular umbrellas modulate the selective toxicity of polyene macrolide antifungals","volume":"29","author":"Skwarecki","year":"2018","journal-title":"Bioconjug. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1006\/bbrc.1993.1153","article-title":"Anti-Candida activity of cispentacin: The active transport by amino acid permeases and possible mechanisms of action","volume":"190","author":"Capobianco","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.7164\/antibiotics.42.1756","article-title":"Cispentacin, a new antifungal antibiotic. II. In vitro and in vivo antifungal activities","volume":"42","author":"Oki","year":"1989","journal-title":"J. Antibiot."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1099\/00221287-143-2-397","article-title":"Functional reconstitution of a purified proline permease from Candida albicans: Interaction with the antifungal cispentacin","volume":"143","author":"Jethwaney","year":"1997","journal-title":"Microbiology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1128\/AAC.42.7.1581","article-title":"Decreased accumulation or increased isoleucyl-tRNA synthetase activity confers resistance to the cyclic beta-amino acid BAY 10-8888 in Candida albicans and Candida tropicalis","volume":"42","author":"Ziegelbauer","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/bdd.429","article-title":"The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro","volume":"26","author":"Parnham","year":"2005","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1021\/bc034007s","article-title":"Enhanced hydrolytic stability and water solubility of an aromatic nitrogen mustard by conjugation with molecular umbrellas","volume":"14","author":"Vijayaraghavan","year":"2003","journal-title":"Bioconjug. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1021\/mp2005033","article-title":"Exploiting dendrimer multivalency to combat emerging and re-emerging infectious diseases","volume":"9","author":"Mintzer","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1021\/bc500277v","article-title":"Molecular umbrella-amphotericin B conjugates","volume":"25","author":"Janout","year":"2014","journal-title":"Bioconjug. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1128\/AAC.42.12.3065","article-title":"Multiple molecular mechanisms contribute to a stepwise development of fluconazole resistance in clinical Candida albicans strains","volume":"42","author":"Franz","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","unstructured":"Clinical and Laboratory Standards Institute (2008). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Clinical and Laboratory Standards Institute. [3rd ed.]. Approved Standard M27-A3."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"669","DOI":"10.7164\/antibiotics.57.669","article-title":"Studies of the effects of antifungal cationic derivatives of amphotericin B on human erythrocytes","volume":"57","author":"Cybulska","year":"2004","journal-title":"J. Antibiot."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/18\/5475\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:59:09Z","timestamp":1760165949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/18\/5475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,8]]},"references-count":26,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["molecules26185475"],"URL":"https:\/\/doi.org\/10.3390\/molecules26185475","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,8]]}}}