The bacterial cell envelope as delimiter of anti infective bioavailability An in vitro permeation model of the Gram negative bacterial inner membrane.
Gram negative bacteria possess a unique and complex cell envelope, composed of an inner and outer membrane separated by an intermediate cell wall containing periplasm. This tripartite structure acts intrinsically as a significant biological barrier, often limiting the permeation of anti infectives, and so preventing such drugs from reaching their target. Furthermore, identification of the specific permeation limiting envelope component proves difficult in the case of many anti infectives, due to the challenges associated with isolation of individual cell envelope structures in bacterial culture. The development of an in vitro permeation model of the Gram negative inner membrane, prepared by repeated coating of physiologically relevant phospholipids on Transwell(r) filter inserts, is therefore reported, as a first step in the development of an overall cell envelope model. Characterization and permeability investigations of model compounds as well as anti infectives confirmed the suitability of the model for quantitative and kinetically resolved permeability assessment, and additionally confirmed the importance of employing bacteria specific base materials for more accurate mimicking of the inner membrane lipid composition both advantages compared to the majority of existing in vitro approaches. Additional incorporation of further elements of the Gram negative bacterial cell envelope could ultimately facilitate model application as a screening tool in anti infective drug discovery or formulation development.
Journal of controlled release official journal of the Controlled Release Society