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The bacterial cell envelope as delimiter of anti-infective bioavailability - An in vitro permeation model of the Gram-negative bacterial inner membrane.
Graef, Florian Vukosavljevic, Branko Michel, Jean-Philippe Wirth, Marius Ries, Oliver De Rossi, Chiara Windbergs, Maike Rosilio, Véronique Ducho, Christian Gordon, Sarah
Graef, Florian
Vukosavljevic, Branko
Michel, Jean-Philippe
Wirth, Marius
Ries, Oliver
De Rossi, Chiara
Windbergs, Maike
Rosilio, Véronique
Ducho, Christian
Gordon, Sarah
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original manuscript
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Abstract
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®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.
Citation
The bacterial cell envelope as delimiter of anti-infective bioavailability - An in vitro permeation model of the Gram-negative bacterial inner membrane. 2016, 243:214-224 J Control Release
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PubMed Central ID
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Article
Language
en
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Series/Report no.
ISSN
1873-4995