TY - JOUR
T1 - The bacterial cell envelope as delimiter of anti-infective bioavailability - an in vitro permeation model of the Gram-negative bacterial inner membrane
AU - Graef, Florian
AU - Vukosavljevic, Branko
AU - Michel, Jean Philippe
AU - Wirth, Marius
AU - Ries, Oliver
AU - De Rossi, Chiara
AU - Windbergs, Maike
AU - Rosilio, Véronique
AU - Ducho, Christian
AU - Gordon, Sarah
AU - Lehr, Claus Michael
N1 - Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016/12/10
Y1 - 2016/12/10
N2 - 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.
AB - 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.
KW - Gram-negative bacterial cell envelope
KW - In vitro permeation model
KW - Permeability investigations
KW - Permeation kinetics
UR - http://www.scopus.com/inward/record.url?scp=84992560093&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2016.10.018
DO - 10.1016/j.jconrel.2016.10.018
M3 - Article
C2 - 27769806
AN - SCOPUS:84992560093
SN - 0168-3659
VL - 243
SP - 214
EP - 224
JO - Journal of Controlled Release
JF - Journal of Controlled Release
ER -