Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland.
Department of Pharmacology, Medical University of Gdansk, Debowa 23, 80-204, Gdansk, Poland.
Sci Rep. 2019 Mar 1;9(1):3247. doi: 10.1038/s41598-019-40103-w.
In the presented study, transportan 10 (TP10), an amphipathic cell penetrating peptide (CPP) with high translocation activity, was conjugated with vancomycin (Van), which is known for poor access to the intracellular bacteria and the brain. The antibacterial activity of the conjugates was tested on selected clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus sp. It turned out that all of them had superior antimicrobial activity in comparison to that of free Van, which became visible particularly against clinical MRSA strains. Furthermore, one of the conjugates was tested against MRSA - infected human cells. With respect to them, this compound showed high bactericidal activity. Next, the same conjugate was screened for its capacity to cross the blood brain barrier (BBB). Therefore, qualitative and quantitative analyses of the conjugate's presence in the mouse brain slices were carried out after its iv administration. They indicated the conjugate's presence in the brain in amount >200 times bigger than that of Van. The conjugates were safe with respect to erythrocyte toxicity (erythrocyte lysis assay). Van in the form of a conjugate with TP10 acquires superior pharmacodynamic and pharmacokinetic.
在本研究中，转运肽 10（TP10）是一种具有高转位活性的两亲性细胞穿透肽（CPP），与万古霉素（Van）结合，Van 已知难以进入细胞内细菌和大脑。对所选耐甲氧西林金黄色葡萄球菌（MRSA）和肠球菌属临床株的抗菌活性进行了测试。结果表明，所有这些与游离万古霉素相比都具有优越的抗菌活性，这在对抗临床 MRSA 菌株时尤为明显。此外，其中一种缀合物被测试对 MRSA 感染的人细胞的作用。对这些细胞，该化合物表现出很高的杀菌活性。接下来，对相同的缀合物进行了筛选，以研究其穿过血脑屏障（BBB）的能力。因此，在静脉注射后，对该缀合物在小鼠脑片中的存在进行了定性和定量分析。结果表明，与万古霉素相比，该缀合物在大脑中的含量高出 200 多倍。该缀合物对红细胞毒性（红细胞溶解试验）是安全的。以与 TP10 结合的形式存在的万古霉素具有优越的药效学和药代动力学。
