{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:10:54Z","timestamp":1788581454417,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"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-2016\/23\/B\/NZ7\/01223"],"award-info":[{"award-number":["UMO-2016\/23\/B\/NZ7\/01223"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans\u2192 all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic\/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.<\/jats:p>","DOI":"10.3390\/ijms221810108","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics"],"prefix":"10.3390","volume":"22","author":[{"given":"Julia","family":"Borzyszkowska-Bukowska","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":"Justyna","family":"G\u00f3rska","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"}]},{"given":"Pawe\u0142","family":"Szczeblewski","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\/0000-0003-4868-2381","authenticated-orcid":false,"given":"Tomasz","family":"Laskowski","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\/0000-0003-0833-5596","authenticated-orcid":false,"given":"Iwona","family":"Gabriel","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"}]},{"given":"Jakub","family":"Jurasz","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"}]},{"given":"Katarzyna","family":"Koz\u0142owska-Tylingo","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\/0000-0001-8291-5148","authenticated-orcid":false,"given":"Piotr","family":"Szweda","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\/0000-0003-2616-4495","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":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1128\/br.37.2.166-196.1973","article-title":"Chemistry and biology of polyene macrolide antibiotics","volume":"37","year":"1973","journal-title":"Bacteriol. Rev."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","unstructured":"Oroshnik, W., and Mebane, A.D. (1963). The Polyene Antifungal Antibiotics. Progress in the Chemistry of Organic Natural Products\/Progr\u00e8s Dans La Chimie Des Substances Organiques Naturelles, Springer.","DOI":"10.1007\/978-3-7091-7149-3_2"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"459","DOI":"10.2174\/138920009788898019","article-title":"Amphotericin B and its new derivatives-mode of action","volume":"10","author":"Czub","year":"2009","journal-title":"Curr. Drug Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eabd5230","DOI":"10.1126\/sciadv.abd5230","article-title":"Polarization-sensitive stimulated Raman scattering imaging resolves amphotericin B orientation in Candida membrane","volume":"7","author":"Dong","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_6","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_7","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 Central Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18266","DOI":"10.1021\/ja1074344","article-title":"How Do Sterols Determine the Antifungal Activity of Amphotericin B? Free Energy of Binding between the Drug and Its Membrane Targets","volume":"132","author":"Neumann","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1128\/AAC.36.11.2518","article-title":"Effects of aggregation and solvent on the toxicity of amphotericin B to human erythrocytes","volume":"36","author":"Legrand","year":"1992","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1002\/chem.200701237","article-title":"Synthesis and in vitro biological properties of novel cationic derivatives of amphotericin B","volume":"14","author":"Paquet","year":"2008","journal-title":"Chemistry"},{"key":"ref_11","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_12","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-Dami\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_13","doi-asserted-by":"crossref","first-page":"128","DOI":"10.2174\/1573406415666181203114629","article-title":"The substantial improvement of Amphotericin B selective toxicity upon modification of mycosamine with bulky substituents","volume":"16","author":"Borowski","year":"2020","journal-title":"Med. Chem."},{"key":"ref_14","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":"14","author":"Tevyashova","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_15","first-page":"270","article-title":"The influence of electric charge of aromatic heptaene macrolide antibiotics on their activity on biological and lipidic model membranes","volume":"24","author":"Cybulska","year":"1983","journal-title":"Mol. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1021\/acs.jnatprod.7b00821","article-title":"Light-Induced Transformation of the Aromatic Heptaene Antifungal Antibiotic Candicidin D into Its All-Trans Isomer","volume":"81","author":"Szczeblewski","year":"2018","journal-title":"J. Nat. Prod."},{"key":"ref_17","unstructured":"CLSI (2017). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, Clinical and Laboratory Standards Institute. [4th ed.]. CLSI standard M27."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sowi\u0144ski, P., Pawlak, J., Borowski, E., and Gariboldi, P. (1995). ChemInform Abstract: Stereostructure of Gedamycin (I). ChemInform, 26.","DOI":"10.1002\/chin.199526271"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.7164\/antibiotics.42.1631","article-title":"The structure of vacidin A, an aromatic heptaene macrolide antibiotic. I. Complete assignment of the 1H NMR spectrum and geometry of the polyene chromophore","volume":"42","author":"Gariboldi","year":"1989","journal-title":"J. Antibiot."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.7164\/antibiotics.42.1639","article-title":"The structure of vacidin A, an aromatic heptaene macrolide antibiotic. II. Stereochemistry of the antibiotic","volume":"42","author":"Gariboldi","year":"1989","journal-title":"J. Antibiot."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/ja.2015.17","article-title":"The stereostructure of candicidin D","volume":"68","author":"Szwarc","year":"2015","journal-title":"J. Antibiot."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/262698a0","article-title":"Single ionic channels induced in lipid bilayers by polyene antibiotics amphotericin B and nystatine","volume":"262","author":"Ermishkin","year":"1976","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"32780","DOI":"10.1038\/srep32780","article-title":"Molecular organization, localization and orientation of antifungal antibiotic amphotericin B in a single lipid bilayer","volume":"6","author":"Sagan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_24","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."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types","volume":"114","author":"Klauda","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_26","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2013). Gaussian 09, Revision D.01, Gaussian Inc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1002\/jcc.23422","article-title":"Rapid parameterization of small molecules using the force field toolkit","volume":"34","author":"Mayne","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1002\/jcc.23702","article-title":"CHARMM-GUI membrane builder toward realistic biological membrane simulations","volume":"35","author":"Wu","year":"2014","journal-title":"J. Comput. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.cpc.2013.09.018","article-title":"PLUMED 2: New feathers for an old bird","volume":"185","author":"Tribello","year":"2014","journal-title":"Comput. Phys. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"12562","DOI":"10.1073\/pnas.202427399","article-title":"Escaping free-energy minima","volume":"99","author":"Laio","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: AnN\u22c5log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/wcms.66","article-title":"Umbrella Sampling","volume":"1","year":"2011","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/jcc.540130812","article-title":"The weighted histogram analysis method for free-energy calculations on biomolecules. I. The method","volume":"13","author":"Kumar","year":"1992","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10108\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:01Z","timestamp":1760166121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":36,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810108"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810108","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]}}}