{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T09:22:49Z","timestamp":1789204969200,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Gda\u0144sk","award":["DS-531-T064-D492-24"],"award-info":[{"award-number":["DS-531-T064-D492-24"]}]},{"name":"University of Gda\u0144sk","award":["BMN 539-T060-B147-24"],"award-info":[{"award-number":["BMN 539-T060-B147-24"]}]},{"name":"University of Gda\u0144sk","award":["01-65023"],"award-info":[{"award-number":["01-65023"]}]},{"name":"University of Gda\u0144sk","award":["0005239"],"award-info":[{"award-number":["0005239"]}]},{"name":"Medical University of Gda\u0144sk","award":["DS-531-T064-D492-24"],"award-info":[{"award-number":["DS-531-T064-D492-24"]}]},{"name":"Medical University of Gda\u0144sk","award":["BMN 539-T060-B147-24"],"award-info":[{"award-number":["BMN 539-T060-B147-24"]}]},{"name":"Medical University of Gda\u0144sk","award":["01-65023"],"award-info":[{"award-number":["01-65023"]}]},{"name":"Medical University of Gda\u0144sk","award":["0005239"],"award-info":[{"award-number":["0005239"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Vancomycin (Van) is a glycopeptide antibiotic commonly used as a last resort for treating life-threatening infections caused by multidrug-resistant bacterial strains, such as Staphylococcus aureus and Enterococcus spp. However, its effectiveness is currently limited due to the rapidly increasing number of drug-resistant clinical strains and its inherent cytotoxicity and poor penetration into cells and specific regions of the body, such as the brain. One of the most promising strategies to enhance its efficacy appears to be the covalent attachment of cell-penetrating peptides (CPPs) to the Van structure. In this study, a series of vancomycin conjugates with CPPs\u2014such as TP10, Tat (47\u201357), PTD4, and Arg9\u2014were designed and synthesized. These conjugates were tested for antimicrobial activity against four reference strains (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa) and two clinical drug-resistant strains: methicillin-resistant S. aureus and vancomycin-resistant E. faecium. In addition, cytotoxicity tests (using a human fibroblast cell line) and blood\u2013brain barrier (BBB) permeability tests (using a parallel artificial membrane permeability assay\u2014PAMPA-BBB assay) were conducted for selected compounds. Our research demonstrated that conjugation of Van with CPPs, particularly with Tat (47\u201357), Arg9, or TP10, significantly enhances its antimicrobial activity against Gram-positive bacteria such as S. aureus and Enterococcus spp., reduces its cytotoxicity, and improves its access to brain tissues. We conclude that these findings provide a strong foundation for the design of novel antimicrobial agents effective in treating infections caused by drug-resistant staphylococcal and enterococcal strains, while also being capable of crossing the BBB.<\/jats:p>","DOI":"10.3390\/molecules29235519","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T04:21:36Z","timestamp":1732249296000},"page":"5519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["New Conjugates of Vancomycin with Cell-Penetrating Peptides\u2014Synthesis, Antimicrobial Activity, Cytotoxicity, and BBB Permeability Studies"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1945-194X","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Ruczy\u0144ski","sequence":"first","affiliation":[{"name":"Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5366-1055","authenticated-orcid":false,"given":"Katarzyna","family":"Prochera","sequence":"additional","affiliation":[{"name":"Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Ka\u017amierczak","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, Medical University of Gda\u0144sk, D\u0119bowa 25, 80-204 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5023-1531","authenticated-orcid":false,"given":"Katarzyna","family":"Kosznik-Kwa\u015bnicka","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, Medical University of Gda\u0144sk, D\u0119bowa 25, 80-204 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9222-7330","authenticated-orcid":false,"given":"Lidia","family":"Piechowicz","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Faculty of Medicine, Medical University of Gda\u0144sk, D\u0119bowa 25, 80-204 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0269-8620","authenticated-orcid":false,"given":"Piotr","family":"Mucha","sequence":"additional","affiliation":[{"name":"Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6994-4833","authenticated-orcid":false,"given":"Piotr","family":"Rekowski","sequence":"additional","affiliation":[{"name":"Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gda\u0144sk, Wita Stwosza 63, 80-308 Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/ja.2014.144","article-title":"Tackling vancomycin-resistant bacteria with \u2018lipophilic\u2013vancomycin\u2013carbohydrate conjugates\u2019","volume":"68","author":"Yarlagadda","year":"2015","journal-title":"J. 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