{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T01:04:45Z","timestamp":1768871085367,"version":"3.49.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,29]],"date-time":"2024-06-29T00:00:00Z","timestamp":1719619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-20102"],"award-info":[{"award-number":["21-74-20102"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Polyene antibiotics have been used in antifungal therapy since the mid-twentieth century. They are highly valued for their broad spectrum of activity and the rarity of pathogen resistance to their action. However, their use in the treatment of systemic mycoses often results in serious side-effects. Recently, there has been a renewed interest in the development of new antifungal drugs based on polyenes, particularly due to the emergence of highly dangerous pathogenic strains of fungi, such as Candida auris, and the increased incidence of mucormycosis. Considerable understanding has been established regarding the structure\u2013biological activity relationships of polyene antifungals. Yet, no previous studies have examined the effect of introducing quaternized fragments into their molecular structure. In this study, we present a series of amides of amphotericin B, nystatin, and natamycin bearing a quaternized group in the side chain, and discuss their biological properties: antifungal activity, cytotoxicity, and effects on lipid bilayers that mimic fungal and mammalian cell membranes. Our research findings suggest that the nature of the introduced quaternized residue plays a more significant role than merely the introduction of a constant positive charge. Among the tested polyenes, derivatives 4b, 5b, and 6b, which contain a fragment of N-methyl-4-(aminomethyl)pyridinium in their structure, are particularly noteworthy due to their biological activity.<\/jats:p>","DOI":"10.3390\/antibiotics13070608","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T11:33:53Z","timestamp":1719920033000},"page":"608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Study on the Effect of Quaternization of Polyene Antibiotics\u2019 Structures on Their Activity, Toxicity, and Impact on Membrane Models"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2433-5713","authenticated-orcid":false,"given":"Olga","family":"Omelchuk","sequence":"first","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-1011","authenticated-orcid":false,"given":"Anna","family":"Tevyashova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"},{"name":"School of Science, Constructor University, Campus Ring 1, 28759 Bremen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2429-2007","authenticated-orcid":false,"given":"Svetlana","family":"Efimova","sequence":"additional","affiliation":[{"name":"Institute of Cytology, The Russian Academy of Sciences, 4 Tikhoretsky Ave., St. Petersburg 194064, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Grammatikova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Bychkova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Zatonsky","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lyubov","family":"Dezhenkova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9199-7229","authenticated-orcid":false,"given":"Nikita","family":"Savin","sequence":"additional","affiliation":[{"name":"Research Laboratory of Biophysics, National University of Science and Technology \u201cMISIS\u201d, 4 p.1 Leninsky Pr., Moscow 119049, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Solovieva","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Ostroumova","sequence":"additional","affiliation":[{"name":"Institute of Cytology, The Russian Academy of Sciences, 4 Tikhoretsky Ave., St. Petersburg 194064, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6595-0811","authenticated-orcid":false,"given":"Andrey","family":"Shchekotikhin","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"key":"ref_1","first-page":"271","article-title":"Invasive Fungal Infection","volume":"116","author":"Wagener","year":"2019","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.cmi.2019.03.028","article-title":"Resistance of Candida to Azoles and Echinocandins Worldwide","volume":"25","author":"Pristov","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s11908-022-00782-5","article-title":"Antifungal Resistance and the Role of New Therapeutic Agents","volume":"24","author":"Logan","year":"2022","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Madhavan, Y., Sai, K.V., Shanmugam, D.K., Manimaran, A., Guruviah, K., Mohanta, Y.K., Venugopal, D.C., Mohanta, T.K., Sharma, N., and Muthupandian, S. (2022). Current Treatment Options for COVID-19 Associated Mucormycosis: Present Status and Future Perspectives. J. Clin. Med., 11.","DOI":"10.3390\/jcm11133620"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s40121-020-00382-7","article-title":"Sixty Years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections","volume":"10","author":"Cavassin","year":"2021","journal-title":"Infect. Dis. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijfoodmicro.2016.08.006","article-title":"Fungal Strains and the Development of Tolerance against Natamycin","volume":"238","author":"Streekstra","year":"2016","journal-title":"Int. J. Food Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"114969","DOI":"10.1016\/j.addr.2023.114969","article-title":"Reviving the Interest in the Versatile Drug Nystatin: A Multitude of Strategies to Increase Its Potential as an Effective and Safe Antifungal Agent","volume":"199","author":"Sousa","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1021\/acsmedchemlett.1c00538","article-title":"Water-Soluble Nystatin and Derivative","volume":"13","author":"Amir","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8897","DOI":"10.1021\/acs.jmedchem.1c02227","article-title":"Design, Synthesis, and Structure\u2013Activity Relationship Studies of Bisamide Derivatives of Amphotericin B with Potent Efficacy and Low Toxicity","volume":"65","author":"Ma","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Haro-Reyes, T., D\u00edaz-Peralta, L., Galv\u00e1n-Hern\u00e1ndez, A., Rodr\u00edguez-L\u00f3pez, A., Rodr\u00edguez-Fragoso, L., and Ortega-Blake, I. (2022). Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications. Membranes, 12.","DOI":"10.3390\/membranes12070681"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6393","DOI":"10.1074\/jbc.M707821200","article-title":"Natamycin Blocks Fungal Growth by Binding Specifically to Ergosterol without Permeabilizing the Membrane","volume":"283","author":"Welscher","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11156","DOI":"10.1073\/pnas.1203375109","article-title":"Polyene Antibiotic That Inhibits Membrane Transport Proteins","volume":"109","author":"Dijksterhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nchembio.1496","article-title":"Amphotericin Forms an Extramembranous and Fungicidal Sterol Sponge","volume":"10","author":"Anderson","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1021\/acscentsci.1c00148","article-title":"Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides","volume":"7","author":"Guo","year":"2021","journal-title":"ACS Cent. Sci."},{"key":"ref_15","first-page":"337","article-title":"Our Path to Less Toxic Amphotericins","volume":"27","author":"Endo","year":"2016","journal-title":"Synlett"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8488","DOI":"10.1021\/ja403255s","article-title":"C2\u2032-OH of Amphotericin B Plays an Important Role in Binding the Primary Sterol of Human Cells but Not Yeast Cells","volume":"135","author":"Wilcock","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1073\/pnas.1117280109","article-title":"Amphotericin Primarily Kills Yeast by Simply Binding Ergosterol","volume":"109","author":"Gray","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1021\/ol060353o","article-title":"Significant Improvement of Antifungal Activity of Polyene Macrolides by Bisalkylation of the Mycosamine","volume":"8","author":"Paquet","year":"2006","journal-title":"Org. Lett."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00430-014-0343-4","article-title":"Novel Nystatin A1 Derivatives Exhibiting Low Host Cell Toxicity and Antifungal Activity in an in Vitro Model of Oral Candidosis","volume":"203","author":"Salewska","year":"2014","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nchembio.1821","article-title":"Nontoxic Antimicrobials That Evade Drug Resistance","volume":"11","author":"Davis","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1021\/acsinfecdis.2c00237","article-title":"Semisynthetic Amides of Polyene Antibiotic Natamycin","volume":"9","author":"Tevyashova","year":"2023","journal-title":"ACS Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Antill\u00f3n, A., de Vries, A.H., Espinosa-Caballero, M., Falc\u00f3n-Gonz\u00e1lez, J.M., Flores Romero, D., Gonz\u00e1lez\u2013Dami\u00e1n, J., Jim\u00e9nez-Montejo, F.E., Le\u00f3n-Buitimea, A., L\u00f3pez-Ortiz, M., and Maga\u00f1a, R. (2016). An Amphotericin B Derivative Equally Potent to Amphotericin B and with Increased Safety. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162171"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tevyashova, A., Efimova, S., Alexandrov, A., Omelchuk, O., Ghazy, E., Bychkova, E., Zatonsky, G., Grammatikova, N., Dezhenkova, L., and Solovieva, S. (2023). Semisynthetic Amides of Amphotericin B and Nystatin A1: A Comparative Study of In Vitro Activity\/Toxicity Ratio in Relation to Selectivity to Ergosterol Membranes. Antibiotics, 12.","DOI":"10.3390\/antibiotics12010151"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/0005-2736(89)90312-X","article-title":"The Role of the Carboxyl and Amino Groups of Polyene Macrolides in Their Interactions with Sterols and Their Selective Toxicity. A 31P-NMR Study","volume":"980","author":"Debouzy","year":"1989","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1021\/acsinfecdis.0c00068","article-title":"Discovery of Amphamide, a Drug Candidate for the Second Generation of Polyene Antibiotics","volume":"6","author":"Tevyashova","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"98","DOI":"10.6060\/mhc181216s","article-title":"Eremomycin Picolylamides and Their Cationic Lipoglycopeptides: Synthesis and Antimicrobial Properties","volume":"12","author":"Moiseenko","year":"2019","journal-title":"Macroheterocycles"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10006","DOI":"10.1021\/ac503177n","article-title":"Quaternary Ammonium Promoted Ultra Selective and Sensitive Fluorescence Detection of Fluoride Ion in Water and Living Cells","volume":"86","author":"Li","year":"2014","journal-title":"Anal. Chem."},{"key":"ref_29","unstructured":"Arendrup, M.C., Meletiadis, J., Mouton, J.W., Lagrou, K., Pert, H., and Guinea, J. (2020). EUCAST Definitive Document E.DEF 7.3.2 Method for the Determination of Broth Dilution Minimum Inhibitory Concentrations of Antifungal Agents for Yeasts, EUCAST."},{"key":"ref_30","unstructured":"Arendrup, M.C., Guinea, J., Cuenca-Estrella, M., Meletiadis, J., Mouton, J.W., Lagrou, K., and Pert, H. (2020). EUCAST Definitive Document E.DEF 9.3.2 Method for the Determination of Broth Dilution Minimum Inhibitory Concentrations of Antifungal Agents for Conidia Forming Moulds, EUCAST."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1111\/j.1574-6976.2011.00278.x","article-title":"Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, Epidemiology, Pathogenicity and Antifungal Resistance","volume":"36","author":"Silva","year":"2012","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s11046-013-9638-z","article-title":"Candida albicans and Non-C. albicans Candida Species: Comparison of Biofilm Production and Metabolic Activity in Biofilms, and Putative Virulence Properties of Isolates from Hospital Environments and Infections","volume":"175","author":"Ferreira","year":"2013","journal-title":"Mycopathologia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17745","DOI":"10.1038\/s41598-020-74749-8","article-title":"Novel and Potent Antimicrobial Effects of Caspofungin on Drug-Resistant Candida and Bacteria","volume":"10","author":"Sumiyoshi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5216\/rpt.v47i1.52351","article-title":"Biofilm Forming Capability and Antifungal Susceptibility Profile of Candida spp. from blood","volume":"47","year":"2018","journal-title":"Rev. Patol. Trop."},{"key":"ref_35","first-page":"150","article-title":"The Antifungal Effect of Peptides from Hymenoptera Venom and Their Analogs","volume":"6","year":"2011","journal-title":"Cent. Eur. J. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1039\/D2BM00964A","article-title":"Scanning Ion-Conductance Microscopy Technique for Studying the Topography and Mechanical Properties of Candida parapsilosis Yeast Microorganisms","volume":"11","author":"Savin","year":"2023","journal-title":"Biomater. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.burns.2017.08.019","article-title":"Thermal Stability of Mafenide and Amphotericin B Topical Solution","volume":"44","author":"Rizzo","year":"2018","journal-title":"Burns"},{"key":"ref_38","first-page":"239","article-title":"Thermotropic Phase Transitions of Pure Lipids in Model Membranes and Their Modifications by Membrane Proteins","volume":"2","author":"Silvius","year":"1982","journal-title":"Lipid Protein Interact."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1042\/BJ20100516","article-title":"Fluorescent Probe Partitioning in Giant Unilamellar Vesicles of \u2018Lipid Raft\u2019 Mixtures","volume":"430","author":"Juhasz","year":"2010","journal-title":"Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.chemphyslip.2014.07.008","article-title":"Direct Visualization of Solid Ordered Domains Induced by Polyene Antibiotics in Giant Unilamellar Vesicles","volume":"183","author":"Chulkov","year":"2014","journal-title":"Chem. Phys. Lipids"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Efimova, S.S., Tevyashova, A.N., Olsufyeva, E.N., Bykov, E.E., and Ostroumova, O.S. (2017). Pore-Forming Activity of New Conjugate Antibiotics Based on Amphotericin B. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188573"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/BF01868444","article-title":"Single-Length and Double-Length Channels Formed by Nystatin in Lipid Bilayer Membranes","volume":"80","author":"Kleinberg","year":"1984","journal-title":"J. Membr. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1002\/jps.2600640327","article-title":"Synthesis and Biological Properties of Alkyl Esters of Polyene Antibiotics","volume":"64","author":"Bruzzese","year":"1975","journal-title":"J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"eabo2658","DOI":"10.1126\/sciadv.abo2658","article-title":"Amphotericin B Assembles into Seven-Molecule Ion Channels: An NMR and Molecular Dynamics Study","volume":"8","author":"Umegawa","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00249-014-0983-8","article-title":"Recent Progress in the Study of the Interactions of Amphotericin B with Cholesterol and Ergosterol in Lipid Environments","volume":"43","year":"2014","journal-title":"Eur. Biophys. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6355","DOI":"10.1007\/s00253-021-11477-7","article-title":"The Newly Synthesized Thiazole Derivatives as Potential Antifungal Compounds against Candida albicans","volume":"105","author":"Biernasiuk","year":"2021","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"S\u00e6b\u00f8, I.P., Bj\u00f8r\u00e5s, M., Franzyk, H., Helgesen, E., and Booth, J.A. (2023). Optimization of the Hemolysis Assay for the Assessment of Cytotoxicity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032914"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.1073\/pnas.69.12.3561","article-title":"Formation of Bimolecular Membranes from Lipid Monolayers and a Study of Their Electrical Properties","volume":"69","author":"Montal","year":"1972","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/7\/608\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:07:41Z","timestamp":1760108861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/13\/7\/608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,29]]},"references-count":48,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["antibiotics13070608"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics13070608","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,29]]}}}