{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T11:39:19Z","timestamp":1765280359192,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T00:00:00Z","timestamp":1680825600000},"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":["21-64-00006"],"award-info":[{"award-number":["21-64-00006"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Aminoglycosides are one of the first classes of antibiotics to have been used clinically, and they are still being used today. They have a broad spectrum of antimicrobial activity, making them effective against many different types of bacteria. Despite their long history of use, aminoglycosides are still considered promising scaffolds for the development of new antibacterial agents, particularly as bacteria continue to develop resistances to existing antibiotics. We have synthesized a series of 6\u2033-deoxykanamycin A analogues with additional protonatable groups (amino-, guanidino or pyridinium) and tested their biological activities. For the first time we have demonstrated the ability of the tetra-N-protected-6\u2033-O-(2,4,6-triisopropylbenzenesulfonyl)kanamycin A to interact with a weak nucleophile, pyridine, resulting in the formation of the corresponding pyridinium derivative. Introducing small diamino-substituents at the 6\u2033-position of kanamycin A did not significantly alter the antibacterial activity of the parent antibiotic, but further modification by acylation resulted in a complete loss of the antibacterial activity. However, introducing a guanidine residue led to a compound with improved activity against S. aureus. Moreover, most of the obtained 6\u2033-modified kanamycin A derivatives were less influenced by the resistant mechanism associated with mutations of the elongation factor G than the parent kanamycin A. This suggests that modifying the 6\u2033-position of kanamycin A with protonatable groups is a promising direction for the further development of new antibacterial agents with reduced resistances.<\/jats:p>","DOI":"10.3390\/pharmaceutics15041177","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:15:57Z","timestamp":1681096557000},"page":"1177","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synthesis of 6\u2033-Modified Kanamycin A Derivatives and Evaluation of Their Antibacterial Properties"],"prefix":"10.3390","volume":"15","author":[{"given":"Kseniya","family":"Shapovalova","sequence":"first","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgy","family":"Zatonsky","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Grammatikova","sequence":"additional","affiliation":[{"name":"Gause Institute of New Antibiotics, 11 B. Pirogovskaya, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7748-980X","authenticated-orcid":false,"given":"Ilya","family":"Osterman","sequence":"additional","affiliation":[{"name":"Center of Life Sciences, Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, 121205 Moscow, Russia"},{"name":"Center for Translational Medicine, Sirius University of Science and Technology, Olympic Avenue 1, 354340 Sochi, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizaveta","family":"Razumova","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, 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, 119021 Moscow, 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, 119021 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1080\/10408398.2015.1077192","article-title":"Antimicrobial Resistance: A Global Emerging Threat to Public Health Systems","volume":"57","author":"Ferri","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"ofaa276","DOI":"10.1093\/ofid\/ofaa276","article-title":"Drugs for Gram-Negative Bugs from 2010\u20132019: A Decade in Review","volume":"7","author":"Pontefract","year":"2020","journal-title":"Open Forum Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.jiph.2021.02.011","article-title":"Antimicrobial Resistance Threats in the Emerging COVID-19 Pandemic: Where do We Stand?","volume":"14","author":"Ghosh","year":"2021","journal-title":"J. Infect. Public Health."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106324","DOI":"10.1016\/j.ijantimicag.2021.106324","article-title":"Increased Antimicrobial Resistance during the COVID-19 Pandemic","volume":"57","author":"Lai","year":"2021","journal-title":"Int. J. Antimicrob. Agents."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1007\/s11094-021-02510-0","article-title":"Potential for the Development of a New Generation of Aminoglycoside Antibiotics","volume":"55","author":"Tevyashova","year":"2021","journal-title":"Pharm. Chem. J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Menzies, D., Benedetti, A., Paydar, A., Martin, I., Royce, S., Pai, M., Vernon, A., Lienhardt, C., and Burman, W. (2009). Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-analysis. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000146"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1128\/JCM.01947-09","article-title":"Detection by Genotype MTBDRsl Test of Complex Resistance Mechanisms to Second-line Drugs and Ethambutol in Multidrug-resistant Mycobacterium Tuberculosis Complex Isolates","volume":"48","author":"Brossier","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/35030019","article-title":"Functional Insights from the Structure of the 30S Ribosomal Subunit and Its Interactions with Antibiotics","volume":"407","author":"Carter","year":"2000","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1126\/science.274.5291.1367","article-title":"Structure of the A Site of Escherichia coli 16 S Ribosomal RNA Complexed with an Aminoglycoside Antibiotic","volume":"274","author":"Fourmy","year":"1996","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s00253-005-0279-0","article-title":"Molecular Understanding of Aminoglycoside Action and Resistance","volume":"70","author":"Jana","year":"2006","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/0006-291X(78)91493-6","article-title":"Inhibition of Ribosomal Translocation by Aminoglycoside Antibiotics","volume":"83","author":"Cabanas","year":"1978","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2174\/138161207779313731","article-title":"Aminoglycoside-induced Ototoxicity","volume":"13","author":"Selimoglu","year":"2007","journal-title":"Curr. Pharm. Des."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/ki.2010.337","article-title":"New Insights into the Mechanism of Aminoglycoside Nephrotoxicity: An Integrative Point of View","volume":"79","author":"Quiros","year":"2011","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"a027029","DOI":"10.1101\/cshperspect.a027029","article-title":"Aminoglycosides: An Overview","volume":"6","author":"Krause","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_15","first-page":"553","article-title":"Antibiotics in the Pipeline: A Literature Review (2017\u20132020)","volume":"50","author":"Momattin","year":"2021","journal-title":"Infection"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e00932-20","DOI":"10.1128\/mBio.00932-20","article-title":"Parallel Evolution of Tobramycin Resistance across Species and Environments","volume":"11","author":"Scribner","year":"2020","journal-title":"MBio"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3389\/fmicb.2018.00427","article-title":"Parallel Evolution of High Level Aminoglycoside Resistance in Escherichia Coli under Low and High Mutation Supply Rates","volume":"9","author":"Oliveros","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e01835-17","DOI":"10.1128\/AAC.01835-17","article-title":"Mutations in Gene fusA1 as a Novel Mechanism of Aminoglycoside Resistance in Clinical Strains of Pseudomonas aeruginosa","volume":"62","author":"Bolard","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"695","DOI":"10.7164\/antibiotics.25.695","article-title":"BB-K8, a New Semisynthetic Aminoglycoside Antibiotic","volume":"25","author":"Kawaguchi","year":"1972","journal-title":"J. Antibiot."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1039\/C7CS00407A","article-title":"Comprehensive Review of Chemical Strategies for the Preparation of New Aminoglycosides and Their Biological Activities","volume":"47","author":"Chandrika","year":"2018","journal-title":"Chem. Soc. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/(SICI)1521-3773(19980202)37:1\/2<109::AID-ANIE109>3.0.CO;2-0","article-title":"RNA\u2013Aminoglycoside Interactions: Design, Synthesis, and Binding of \u201cAmino-aminoglycosides\u201d to RNA","volume":"37","author":"Wang","year":"1998","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1039\/C8MD00155C","article-title":"Antifungal Amphiphilic Kanamycins: New Life for an Old Drug","volume":"9","author":"Subedi","year":"2018","journal-title":"Med. Chem. Comm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1021\/acsinfecdis.8b00327","article-title":"Development of Fungal Selective Amphiphilic Kanamycin: Cost-effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation","volume":"5","author":"Subedi","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111639","DOI":"10.1016\/j.ejmech.2019.111639","article-title":"Scalable and Cost-effective Tosylation-mediated Synthesis of Antifungal and Fungal Diagnostic 6\u2033-Modified Amphiphilic Kanamycins","volume":"182","author":"Subedi","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.funbio.2017.12.001","article-title":"Suppression of wheat Fusarium Head Blight by Novel Amphiphilic Aminoglycoside Fungicide K20","volume":"122","author":"Takemoto","year":"2018","journal-title":"Fungal Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Alfindee, M.N., Subedi, Y.P., Grilley, M.M., Takemoto, J.Y., and Chang, C.W.T. (2019). Antifungal Activities of 4\u2033,6\u2033-Disubstituted Amphiphilic Kanamycins. Molecules, 24.","DOI":"10.3390\/molecules24101882"},{"key":"ref_27","unstructured":"Clinical and Laboratory Standards Institute (CLSI) (2015). Methods for Dilution Antimicrobial Susceptibility Tests for bacteria that Grow Aerobically, Clinical and Laboratory Standards Institute (CLSI). [10th ed.]. Approved Standard, (M07-A10)."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2006.0008","DOI":"10.1038\/msb4100050","article-title":"Construction of Escherichia coli K-12 In-frame, Single-gene Knockout Mutants: The Keio Collection","volume":"2","author":"Baba","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6640","DOI":"10.1073\/pnas.120163297","article-title":"One-step Inactivation of Chromosomal Genes in Escherichia Coli K-12 Using PCR Products","volume":"97","author":"Datsenko","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1261\/rna.039792.113","article-title":"Studies of Translational Misreading in vivo Show that the Ribosome Very Efficiently Discriminates against Most Potential Errors","volume":"20","author":"Manickam","year":"2014","journal-title":"RNA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9078","DOI":"10.1016\/j.tet.2008.07.022","article-title":"Regioselective Modification of Amino Groups in Aminoglycosides Based on Cyclic Carbamate Formation","volume":"64","author":"Chen","year":"2008","journal-title":"Tetrahedron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1016\/j.bmcl.2007.04.065","article-title":"Synthesis and Antibacterial Activity of 5-Deoxy-5-Episubstituted Arbekacin Derivatives","volume":"17","author":"Hiraiwa","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1021\/jm00108a035","article-title":"New Derivatives of Kanamycin B Obtained by Modifications and Substitutions in Position 6\u2033. 1. Synthesis and Microbiological Evaluation","volume":"34","author":"Delcourt","year":"1991","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1021\/acs.macromol.7b02751","article-title":"Amine-functionalized Polylactide\u2013PEG Copolymers","volume":"51","author":"Erdogan","year":"2018","journal-title":"Macromolecules"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1070\/RCR4977","article-title":"Progress in the Medicinal Chemistry of Organoboron Compounds","volume":"90","author":"Tevyashova","year":"2021","journal-title":"Russ. Chem. Rev."},{"key":"ref_36","first-page":"1655","article-title":"Optimisation of the Synthesis of Guanidines from Amines via Nitroguanidines Using 3, 5-Dimethyl-N-nitro-1H-pyrazole-1-carboxamidine","volume":"10","author":"Golding","year":"2004","journal-title":"Synthesis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1021\/cb3005116","article-title":"Aminoglycoside Antibiotics in the 21st Century","volume":"8","author":"Becker","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1128\/AAC.01034-06","article-title":"Overexpression And Initial Characterization of The Chromosomal Aminoglycoside 3\u2019-O-Phosphotransferase APH(3\u2019)-Iib from Pseudomonas Aeruginosa","volume":"51","author":"Hainrichson","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1093\/dnares\/dsu032","article-title":"Genomic Analysis Reveals Distinct Concentration-dependent Evolutionary Trajectories for Antibiotic Resistance in Escherichia Coli","volume":"21","author":"Mogre","year":"2014","journal-title":"DNA Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.1534\/g3.117.300284","article-title":"Modulation of Global Transcriptional Regulatory Networks as a Strategy for Increasing Kanamycin Resistance of the Translational Elongation Factor-G Mutants in Escherichia Coli","volume":"7","author":"Mogre","year":"2017","journal-title":"Genes Genomes Genet."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Alfieri, A., Franco, S.D., Donatiello, V., Maffei, V., Fittipaldi, C., Fiore, M., Coppolino, F., Sansone, P., Pace, M.C., and Passavanti, M.B. (2022). Plazomicin against Multidrug-Resistant Bacteria: A Scoping Review. Life, 12.","DOI":"10.3390\/life12121949"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Terren, M., Taccani, M., and Pregnolato, M. (2021). New Antibiotics for Multidrug-Resistant Bacterial Strains: Latest Research Developments and Future Perspectives. Molecules, 26.","DOI":"10.3390\/molecules26092671"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.3389\/fmicb.2018.02153","article-title":"The Role of Outer Membrane Proteins and Lipopolysaccharides for the Sensitivity of Escherichia coli to Antimicrobial Peptides","volume":"9","author":"Ebbensgaard","year":"2018","journal-title":"Front Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6880","DOI":"10.1093\/nar\/gkab495","article-title":"Mechanistic Insights into Translation Inhibition by Aminoglycoside Antibiotic Arbekacin","volume":"49","author":"Parajuli","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/4\/1177\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:11:56Z","timestamp":1760123516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/4\/1177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,7]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["pharmaceutics15041177"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15041177","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2023,4,7]]}}}