Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, 330013, China.
School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, 418000, China.
Dalton Trans. 2022 Oct 11;51(39):14980-14992. doi: 10.1039/d2dt01531e.
The wide spread of drug-resistant bacteria, especially methicillin-resistant (MRSA), poses a tremendous threat to global health. Of particular concern, resistance to vancomycin, linezolid, and daptomycin has already been reported in clinical MRSA strains. New antibacterial agents are urgently needed to overcome this crisis. Here, we designed and synthesized a series of ruthenium-based antibacterial agents targeting bacterial membrane integrity. Structure-activity relationship studies demonstrated that both the lipophilicity/hydrophilicity ratio and biphenyl group play an important role in elevating the antibacterial activity. To characterize the antibacterial mechanism, we combined scanning electron microscopy, propidium iodide dyeing, and DNA leakage assays. The results demonstrated that Ru2 could destroy the integrity of bacterial cell membranes. In addition, Ru2 can efficiently inhibit biofilm formation and α-hemolysin secretion from . Finally, in both a mouse skin infection model and a wax worm infection model, Ru2 showed significant antibacterial activity . Moreover, the Ru2 complex was almost non-toxic. Thus, this work demonstrated that ruthenium-based complexes bearing a biphenyl group are promising agents to combat bacterial infection.
耐药菌（尤其是耐甲氧西林金黄色葡萄球菌，MRSA）的广泛传播对全球健康构成了巨大威胁。值得特别关注的是，临床分离的 MRSA 菌株已经出现了对万古霉素、利奈唑胺和达托霉素的耐药性。急需新型抗菌药物来应对这一危机。在这里，我们设计并合成了一系列针对细菌膜完整性的基于钌的抗菌剂。构效关系研究表明，亲脂性/亲水性比和联苯基团都对提高抗菌活性起着重要作用。为了表征抗菌机制，我们结合了扫描电子显微镜、碘化丙啶染色和 DNA 泄漏实验。结果表明，Ru2 可以破坏细菌细胞膜的完整性。此外，Ru2 可以有效抑制生物膜的形成和α-溶血素从 的分泌。最后，在小鼠皮肤感染模型和黄粉虫感染模型中，Ru2 都表现出了显著的抗菌活性。而且，Ru2 配合物的毒性几乎可以忽略不计。因此，这项工作表明，含有联苯基团的基于钌的配合物是对抗细菌感染有前途的药物。
