Studies on the effects of carbapenems on leukocyte-endothelial cell interaction in models of pulmonary inflammation and viral infection

亚胺培南是一种来自β-内酰胺类的保留抗生素，它干扰细菌细胞壁的合成，从而对广泛的细菌具有杀菌作用。亚胺培南在临床上用于治疗严重感染，如败血症。在初步实验中，我们能够证明，在脂多糖诱导的小鼠肺部炎症模型中，100 mg/kg的亚胺培南能显著减少细支气管肺泡灌洗液中各种免疫细胞和红细胞的数量。亚胺培南还能显著抑制血清中的炎症介质。与单独使用亚胺培南相比，当小鼠接受亚胺培南和代谢抑制剂西司他丁(Zienam)的固定组合治疗时，对白细胞迁移和血清标志物的影响更加明显。此外，在这种疾病模型中，临床相关剂量的齐能南20 mg/kg是有效的。在细胞系统中，亚胺培南和齐能显著降低原代人单核细胞与人内皮细胞的黏附。我们的假设是，白细胞与血管内皮细胞的黏附和迁移受到一种未知机制的强烈抑制，这种机制与亚胺培南的抗菌作用无关。在第一个子项目中，将使用内皮模型系统详细描述亚胺培南对免疫细胞黏附和迁移的影响，并对其潜在机制进行研究。利用亚胺培南的衍生物，我们希望在本项目的药物化学部分研究能否将母体化合物亚胺培南的抗炎作用与其抗菌作用分开，并通过进一步的结构修饰来潜在地增加抗炎作用的问题。此外，我们希望利用脂多糖诱导的肺部炎症和病毒感染的小鼠模型来更详细地表征亚胺培南的抗炎作用。根据这一应用的新发现，一些临床上高度相关的抗生素可以根据它们的免疫调节作用更好地进行靶向。此外，基于对亚胺培南靶标结构的了解，亚胺培南对免疫细胞的黏附和迁移的调节非常重要，通过基于结构的药物设计可以开发新的候选药物(在结构上不同于亚胺培南)。

Imipenem is a reserve antibiotic from the class of β-lactams that interfere with bacterial cell wall synthesis and thus have a bactericidal effect on a broad spectrum of germs. Imipenem is used intravenously in the clinic for severe infections such as sepsis. In preliminary experiments, we were able to show that in the mouse model of LPS-induced pulmonary inflammation, the administration of 100 mg/kg imipenem resulted in a significantly reduced number of various immune cells and erythrocytes in the bronchio-alveolar lavage. Imipenem also significantly inhibited inflammatory mediators in serum. The effects on leukocyte migration and serum markers were more pronounced when mice were treated with the fixed combination of imipenem and the metabolisation inhibitor cilastatin (Zienam) compared to imipenem administered alone. In addition, clinically relevant doses of 20 mg/kg zienam were therapeutically effective in this disease model. In the cellular system, imipenem and zienam significantly decreased the adhesion of primary human monocytes to human endothelial cells. Our hypothesis is that the adhesion and migration of leukocytes to and through the vascular endothelium is strongly inhibited by an unknown mechanism that is not related to the antibiotic effect of imipenem. In the first subproject, the effect of imipenem on immune cell adhesion and migration will be characterized in detail using a model system of the endothelium and the underlying mechanism will be investigated. Using imipenem derivatives, we would like to investigate in the medicinal chemistry part of this project whether the anti-inflammatory of the parent compound imipenem can be separated from its antibiotic effect with the question of a potential increase of anti-inflammatory effects by further structural modifications. Moreover, we want to characterize in more detail the anti-inflammatory effects of imipenem using a mouse model of LPS-induced pulmonary inflammation and also viral infection. Based on the new findings from this application, some clinically highly relevant antibiotics could be better targeted according to their immunomodulatory effects. In addition, based on the knowledge of the structure of the target of imipenem, which should be highly important for the regulation of immune cell adhesion and migration, novel drug candidates (structurally different from imipenem) could be developed by means of structure-based drug design.