{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T05:21:18Z","timestamp":1765862478694,"version":"3.48.0"},"reference-count":60,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T00:00:00Z","timestamp":1765584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austrian Science Foundation"},{"DOI":"10.13039\/501100009057","name":"University of Graz","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009057","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Land Steiermark Zukunftsfonds","award":["1109"],"award-info":[{"award-number":["1109"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The macrolide antibiotic telithromycin was developed to avoid common antibiotic resistances, yet it has been recently withdrawn from the European market due to severe side effects. Both side effects and the effectiveness of a drug can be related to the strength of its interaction with human serum albumin (HSA). However, as of yet, interactions between telithromycin and HSA have not been thoroughly studied. In this work, we evaluate the interaction strength and structural details of telithromycin and HSA via diffusion ordered spectroscopy (DOSY) and transferred NOE measurements. The binding strengths are compared with those of related macrolides. Our results show that the interaction strength increases with the decreasing polarity of the side chains in the antibiotic. Among the tested macrolide antibiotics, telithromycin interacted the strongest with HSA. Structure calculations based on transferred NOEs, using DFT calculations, show that telithromycin adopts a specific conformation upon binding, which shields the polar moieties attached to the aglycon and enables more hydrophobic interactions with HSA.<\/jats:p>","DOI":"10.3390\/ijms262412005","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T09:36:39Z","timestamp":1765791399000},"page":"12005","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of the Binding of the Macrolide Antibiotic Telithromycin to Human Serum Albumin by NMR Spectroscopy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0411-3403","authenticated-orcid":false,"given":"Markus","family":"Rotzinger","sequence":"first","affiliation":[{"name":"Institute of Chemistry, University of Graz, Heinrichstra\u00dfe 28, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1148-5536","authenticated-orcid":false,"given":"Peter","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Graz, Heinrichstra\u00dfe 28, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Muhry","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Graz, Heinrichstra\u00dfe 28, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina","family":"Stadler","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Graz, Heinrichstra\u00dfe 28, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Daniel","family":"Boese","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Graz, Heinrichstra\u00dfe 28, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Predrag","family":"Novak","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1682-1594","authenticated-orcid":false,"given":"Klaus","family":"Zangger","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, University of Graz, Heinrichstra\u00dfe 28, 8010 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"636157","DOI":"10.1155\/2012\/636157","article-title":"Macrolide Therapy in Chronic Inflammatory Diseases","volume":"2012","author":"Kwiatkowska","year":"2012","journal-title":"Mediat. Inflamm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.jmb.2004.07.095","article-title":"The Structural Basis of Macrolide\u2013Ribosome Binding Assessed Using Mutagenesis of 23S rRNA Positions 2058 and 2059","volume":"342","author":"Pfister","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sivapalasingam, S., and Steigbigel, N.H. (2015). Macrolides, Clindamycin, and Ketolides. Mandell, Douglas, and Bennett\u2019s Principles and Practice of Infectious Diseases, Elsevier.","DOI":"10.1016\/B978-1-4557-4801-3.00029-1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"357","DOI":"10.2307\/30147135","article-title":"Azithromycin and Clarithromycin: Overview and Comparison with Erythromycin","volume":"13","author":"Whitman","year":"1992","journal-title":"Infect. Control Hosp. Epidemiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0924-8579(01)00407-1","article-title":"Macrolide Resistance Mechanisms in Gram-Positive Cocci","volume":"18","year":"2001","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1517\/13543784.8.8.1171","article-title":"New Research in Macrolides and Ketolides since 1997","volume":"8","author":"Bryskier","year":"1999","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2165\/00003495-200161060-00016","article-title":"Telithromycin","volume":"61","author":"Figgitt","year":"2001","journal-title":"Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bryskier, A. (2005). Ketolides. Antimicrobial Agents, John Wiley & Sons, Ltd.","DOI":"10.1128\/9781555815929"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.idc.2004.04.010","article-title":"Macrolides and Ketolides: Azithromycin, Clarithromycin, Telithromycin","volume":"18","author":"Zuckerman","year":"2004","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1128\/AAC.45.1.170-175.2001","article-title":"Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses","volume":"45","author":"Namour","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1093\/jac\/46.5.741","article-title":"Pharmacokinetics and Comparative Effects of Telithromycin (HMR 3647) and Clarithromycin on the Oropharyngeal and Intestinal Microflora","volume":"46","author":"Edlund","year":"2000","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4276","DOI":"10.1128\/JB.185.14.4276-4279.2003","article-title":"Structural Insight into the Antibiotic Action of Telithromycin against Resistant Mutants","volume":"185","author":"Berisio","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"415","DOI":"10.7326\/0003-4819-144-6-200503210-00121","article-title":"Brief Communication: Severe Hepatotoxicity of Telithromycin: Three Case Reports and Literature Review","volume":"144","author":"Clay","year":"2006","journal-title":"Ann. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1212\/01.wnl.0000247741.72466.8c","article-title":"Myasthenia Gravis Exacerbation or Unmasking Associated with Telithromycin Treatment","volume":"67","author":"Perrot","year":"2006","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s40262-012-0018-5","article-title":"The Clinical Relevance of Plasma Protein Binding Changes","volume":"52","author":"Roberts","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wiedermann, C.J. (2021). Hypoalbuminemia as Surrogate and Culprit of Infections. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094496"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/s13054-018-2155-1","article-title":"Pharmacokinetics\u2013Pharmacodynamics Issues Relevant for the Clinical Use of Beta-Lactam Antibiotics in Critically Ill Patients","volume":"22","author":"Veiga","year":"2018","journal-title":"Crit. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14866","DOI":"10.1038\/srep14866","article-title":"Characterization of Plasma Protein Binding Dissociation with Online SPE-HPLC","volume":"5","author":"Li","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1080\/15216540500404093","article-title":"The Extraordinary Ligand Binding Properties of Human Serum Albumin","volume":"57","author":"Fasano","year":"2005","journal-title":"IUBMB Life Int. Union. Biochem. Mol. Biol. Life"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1021\/acsptsci.2c00115","article-title":"Using Human Serum Albumin Binding Affinities as a Proactive Strategy to Affect the Pharmacodynamics and Pharmacokinetics of Preclinical Drug Candidates","volume":"5","author":"Fan","year":"2022","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s11095-018-2551-x","article-title":"Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein","volume":"36","author":"Smith","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lenz, K.D., Klosterman, K.E., Mukundan, H., and Kubicek-Sutherland, J.Z. (2021). Macrolides: From Toxins to Therapeutics. Toxins, 13.","DOI":"10.3390\/toxins13050347"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1128\/AAC.48.12.4650-4653.2004","article-title":"Pharmacokinetics of Telithromycin in Plasma and Soft Tissues after Single-Dose Administration to Healthy Volunteers","volume":"48","author":"Gattringer","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123","DOI":"10.5414\/CPP43123","article-title":"Effect of Ketoconazole on the Pharmacokinetics and Safety of Telithromycin and Clarithromycin in Older Subjects with Renal Impairment","volume":"43","author":"Shi","year":"2005","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.mcna.2011.03.012","article-title":"Review of Macrolides (Azithromycin, Clarithromycin), Ketolids (Telithromycin) and Glycylcyclines (Tigecycline)","volume":"95","author":"Zuckerman","year":"2011","journal-title":"Med. Clin. N. Am."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113843","DOI":"10.1016\/j.ab.2020.113843","article-title":"Ligand Binding to Natural and Modified Human Serum Albumin","volume":"612","author":"Eskew","year":"2021","journal-title":"Anal. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"De Simone, G., Di Masi, A., and Ascenzi, P. (2021). Serum Albumin: A Multifaced Enzyme. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810086"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1440-1681.1975.tb01826.x","article-title":"Spectroscopic Techniques in the Study of Protein Binding. A Fluorescence Technique for the Evaluation of the Albumin Binding and Displacement of Warfarin and Warfarin-Alcohol","volume":"2","author":"Sudlow","year":"1975","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/mabi.201000206","article-title":"Affinity-Based Drug Delivery","volume":"11","author":"Wang","year":"2011","journal-title":"Macromol. Biosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/bs.apcsb.2020.08.003","article-title":"Serum Albumin: Clinical Significance of Drug Binding and Development as Drug Delivery Vehicle","volume":"123","author":"Tayyab","year":"2021","journal-title":"Advances in Protein Chemistry and Structural Biology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.pnmrs.2016.09.001","article-title":"NMR in Drug Discovery: A Practical Guide to Identification and Validation of Ligands Interacting with Biological Macromolecules","volume":"97","author":"Gossert","year":"2016","journal-title":"Prog. Nucl. Magn. Reson. Spectrosc."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5632","DOI":"10.1021\/jm300647f","article-title":"Probing the Interactions of Macrolide Antibiotics with Membrane-Mimetics by NMR Spectroscopy","volume":"55","author":"Kosol","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5231","DOI":"10.1002\/chem.201905599","article-title":"Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs","volume":"26","author":"Danelius","year":"2020","journal-title":"Chem. Eur. J."},{"key":"ref_34","first-page":"211","article-title":"Epitope Mapping of Macrolide Antibiotics to Bovine Serum Albumin by Saturation Transfer Difference NMR Spectroscopy","volume":"80","author":"Novak","year":"2007","journal-title":"Croat. Chem. Acta"},{"key":"ref_35","unstructured":"Webb, G.A. (2017). The Transferred NOE. Modern Magnetic Resonance, Springer International Publishing."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.pnmrs.2016.08.002","article-title":"Detection of Intermolecular NOE Interactions in Large Protein Complexes","volume":"97","author":"Anglister","year":"2016","journal-title":"Prog. Nucl. Magn. Reson. Spectrosc."},{"key":"ref_37","first-page":"402","article-title":"Theory and Applications of the Transferred Nuclear Overhauser Effect to the Study of the Conformations of Small Ligands Bound to Proteins","volume":"48","author":"Clore","year":"1982","journal-title":"J. Magn. Reson."},{"key":"ref_38","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_39","doi-asserted-by":"crossref","first-page":"E5805","DOI":"10.1073\/pnas.1517952112","article-title":"Structural Insights into Species-Specific Features of the Ribosome from the Pathogen Staphylococcus aureus","volume":"112","author":"Eyal","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17733","DOI":"10.1039\/D4RA00718B","article-title":"Analyzing Atomic Scale Structural Details and Nuclear Spin Dynamics of Four Macrolide Antibiotics: Erythromycin, Clarithromycin, Azithromycin, and Roxithromycin","volume":"14","author":"Lodhi","year":"2024","journal-title":"RSC Adv."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5857","DOI":"10.1016\/j.bmc.2009.07.013","article-title":"Free and Bound State Structures of 6-O-Methyl Homoerythromycins and Epitope Mapping of Their Interactions with Ribosomes","volume":"17","author":"Novak","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_42","first-page":"4350","article-title":"Structural and Functional Implications of the Interaction between Macrolide Antibiotics and Bile Acids","volume":"21","author":"Glanzer","year":"2015","journal-title":"Chem. Weinh. Bergstr. Ger."},{"key":"ref_43","unstructured":"(Hyperchem Professional, 2007). Hyperchem Professional, version 8.0.8."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1039\/b508541a","article-title":"Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy","volume":"7","author":"Weigend","year":"2005","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"154104","DOI":"10.1063\/1.3382344","article-title":"A Consistent and Accurate Ab Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu","volume":"132","author":"Grimme","year":"2010","journal-title":"J. Chem. Phys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/jcc.21759","article-title":"Effect of the Damping Function in Dispersion Corrected Density Functional Theory","volume":"32","author":"Grimme","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1103\/PhysRevA.38.3098","article-title":"Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior","volume":"38","author":"Becke","year":"1988","journal-title":"Phys. Rev. A"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional Thermochemistry. III. The Role of Exact Exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_50","unstructured":"(COSMOconf, 2018). COSMOconf, version 4.3."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1021\/ci6005646","article-title":"Generating Conformer Ensembles Using a Multiobjective Genetic Algorithm","volume":"47","author":"Vainio","year":"2007","journal-title":"J. Chem. Inf. Model."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1103\/PhysRevLett.77.3865","article-title":"Generalized Gradient Approximation Made Simple","volume":"77","author":"Perdew","year":"1996","journal-title":"Phys. Rev. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Klamt, A., and Sch\u00fc\u00fcrmann, G. (1993). COSMO: A New Approach to Dielectric Screening in Solvents with Explicit Expressions for the Screening Energy and Its Gradient. J. Chem. Soc. Perkin Trans. 2, 799\u2013805.","DOI":"10.1039\/P29930000799"},{"key":"ref_54","unstructured":"University of Karlsruhe and Forschungszentrum Karlsruhe GmbH (TURBOMOLE, 2024). TURBOMOLE, version 7.9."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1002\/(SICI)1096-987X(19981130)19:15<1746::AID-JCC7>3.0.CO;2-N","article-title":"Performance of Parallel TURBOMOLE for Density Functional Calculations","volume":"19","author":"Ahlrichs","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1063\/1.469408","article-title":"Efficient Molecular Numerical Integration Schemes","volume":"102","author":"Treutler","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1039\/b515623h","article-title":"Accurate Coulomb-Fitting Basis Sets for H to Rn","volume":"8","author":"Weigend","year":"2006","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/0009-2614(95)00621-A","article-title":"Auxiliary Basis Sets to Approximate Coulomb Potentials","volume":"240","author":"Eichkorn","year":"1995","journal-title":"Chem. Phys. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s002140050244","article-title":"Auxiliary Basis Sets for Main Row Atoms and Transition Metals and Their Use to Approximate Coulomb Potentials","volume":"97","author":"Eichkorn","year":"1997","journal-title":"Theor. Chem. Acc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4285","DOI":"10.1039\/b204199p","article-title":"A Fully Direct RI-HF Algorithm: Implementation, Optimised Auxiliary Basis Sets, Demonstration of Accuracy and Efficiency","volume":"4","author":"Weigend","year":"2002","journal-title":"Phys. Chem. Chem. Phys."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12005\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T05:18:54Z","timestamp":1765862334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/24\/12005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,13]]},"references-count":60,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262412005"],"URL":"https:\/\/doi.org\/10.3390\/ijms262412005","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,12,13]]}}}