Ruczyński Jarosław, Prochera Katarzyna, Kaźmierczak Natalia, Kosznik-Kwaśnicka Katarzyna, Piechowicz Lidia, Mucha Piotr, Rekowski Piotr
Laboratory of Chemistry of Biologically Active Compounds, Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland.
Department of Medical Microbiology, Faculty of Medicine, Medical University of Gdańsk, Dębowa 25, 80-204 Gdańsk, Poland.
Molecules. 2024 Nov 22;29(23):5519. doi: 10.3390/molecules29235519.
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 and 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-such as TP10, Tat (47-57), PTD4, and Arg-were designed and synthesized. These conjugates were tested for antimicrobial activity against four reference strains (, , , and ) and two clinical drug-resistant strains: methicillin-resistant and vancomycin-resistant . In addition, cytotoxicity tests (using a human fibroblast cell line) and blood-brain barrier (BBB) permeability tests (using a parallel artificial membrane permeability assay-PAMPA-BBB assay) were conducted for selected compounds. Our research demonstrated that conjugation of Van with CPPs, particularly with Tat (47-57), Arg, or TP10, significantly enhances its antimicrobial activity against Gram-positive bacteria such as and 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.
万古霉素（Van）是一种糖肽类抗生素，通常作为治疗由多重耐药细菌菌株引起的危及生命感染的最后手段，如金黄色葡萄球菌和肠球菌属。然而，由于耐药临床菌株数量的迅速增加以及其固有的细胞毒性和对细胞及身体特定区域（如大脑）的低渗透性，其有效性目前受到限制。提高其疗效最有前景的策略之一似乎是将细胞穿透肽（CPPs）共价连接到万古霉素结构上。在本研究中，设计并合成了一系列与CPPs（如TP10、Tat（47 - 57）、PTD4和Arg）结合的万古霉素共轭物。测试了这些共轭物对四种参考菌株（金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌和屎肠球菌）和两种临床耐药菌株（耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌）的抗菌活性。此外，对选定的化合物进行了细胞毒性测试（使用人成纤维细胞系）和血脑屏障（BBB）通透性测试（使用平行人工膜通透性测定法 - PAMPA - BBB测定法）。我们的研究表明，万古霉素与CPPs（特别是与Tat（47 - 57）、Arg或TP10）结合，可显著增强其对革兰氏阳性菌（如金黄色葡萄球菌和肠球菌属）的抗菌活性，降低其细胞毒性，并改善其进入脑组织的能力。我们得出结论，这些发现为设计有效治疗由耐药葡萄球菌和肠球菌菌株引起的感染且能够穿过血脑屏障的新型抗菌剂提供了坚实的基础。
