There is a dearth of studies focused on understanding pharmacokinetics, pharmacodynamics and toxicodynamics of polymyxins following direct administration to the central nervous system (CNS). In this study, for the first time, untargeted metabolomics were employed to ascertain the perturbations of brain metabolism in the rat cerebral cortex following direct brain injection of 0.75mg/kg polymyxin B (1 and 4 h) through the right lateral ventricle. In the right cortex metabolome, ICV polymyxin B induced a greater perturbation at 1 h compared to negligible effect at 4 h. Pathway enrichment analysis showed that sphingolipid, arginine, and histidine metabolism, together with aminoacyl-tRNA biosynthesis were significantly affected in the right cortex metabolome. Furthermore, intracerebroventricular (ICV) polymyxin B dysregulated the two arms (CDP-choline and CDP-ethanolamine) of the Kennedy pathway that governs the de novo biosynthesis of neuronal phospholipids. Importantly, the key intermediates of metabolic pathways that maintain cellular redox balance (e.g., glutathione metabolism) and mitochondrial function (e.g., electron transport chain) were markedly depleted. The abundance of key metabolites (e.g., N-acetyl-L-glutamate) associated with diverse CNS disorders (e.g., neurodegenerative disease) were also significantly perturbed. The biological significance of these metabolic perturbations on the CNS includes impaired oxidant-antioxidant balance, impaired neuronal lipid homeostasis and mitochondrial dysfunction. Furthermore, ICV polymyxin B caused a significant alteration in the abundance of several metabolic biomarkers associated with cerebral ischemia, oxidative stress as well as certain neurological disorders. These findings may facilitate the development of new pharmacokinetic/pharmacodynamic strategies to attenuate polymyxins ICV related CNS toxicities and stimulate the discovery of safer next-generation polymyxin-like lipopeptide antibiotics.

缺乏专注于了解多粘菌素直接给药于中枢神经系统 (CNS) 后的药代动力学、药效学和毒理学的研究。在这项研究中，首次采用非靶向代谢组学来确定通过右侧脑室直接向脑内注射 0.75mg/kg 多粘菌素 B（1 小时和 4 小时）后大鼠大脑皮层脑代谢的扰动。在右侧皮质代谢组中，ICV 多粘菌素 B 在 1 小时时诱导了更大的扰动，而在 4 小时时的影响可忽略不计。通路富集分析表明，鞘脂、精氨酸和组氨酸代谢以及氨酰-tRNA 生物合成在右侧皮质代谢组中受到显着影响。此外，神经元磷脂的从头生物合成。重要的是，维持细胞氧化还原平衡（例如，谷胱甘肽代谢）和线粒体功能（例如，电子传递链）的代谢途径的关键中间体被显着耗尽。关键代谢物的丰度（例如，N-乙酰基-L-谷氨酸）与多种中枢神经系统疾病（例如神经退行性疾病）相关，也受到显着干扰。这些代谢扰动对中枢神经系统的生物学意义包括氧化-抗氧化平衡受损、神经元脂质稳态受损和线粒体功能障碍。此外，ICV 多粘菌素 B 导致与脑缺血、氧化应激以及某些神经系统疾病相关的几种代谢生物标志物的丰度发生显着变化。这些发现可能有助于开发新的药代动力学/药效学策略，以减轻多粘菌素 ICV 相关的 CNS 毒性，并促进发现更安全的下一代多粘菌素样脂肽抗生素。