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

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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.