The bacterial cell envelope as delimiter of anti-infective bioavailability - An in vitro permeation model of the Gram-negative bacterial inner membrane

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• 作者：Florian Graef^a ; ^{Florian.Graef@hemholtz-hzi.de} ; Branko Vukosavljevic^a ; ^{Branko.Vukosavljevic@helmholtz-hzi.de} ; Jean-Philippe Michel^b ; ^{jean-philippe.michel@u-psud.fr} ; Marius Wirth^c ; ^{marius.wirth@uni-saaland.de} ; Oliver Ries^c ; Chiara De Rossi^a ; ^{Chiara.DeRossi@helmholtz-hzi.de} ; Maike Windbergs^a ; ^{Maike.Windbergs@helmholtz-hzi.de} ; Vé ; ronique Rosilio^b ; ^{veronique.rosilio@u-psud.fr} ; Christian Ducho^c ; ^{christian.ducho@uni-saarland.de} ; Sarah Gordon^a ; ^{Sarah.Gordon@helmholtz-hzi.de} ; Claus-Michael Lehr^a ; ^d ; ^{Claus-Michael.Lehr@helmholtz-hzi.de}
• 关键词：CL ; cardiolipin ; ER ; electrical resistance ; IM ; inner membrane ; KRB ; Krebs-Ringer buffer ; LC ; liquid condensed ; LE ; liquid expanded ; MIC ; minimal inhibitory concentration ; OM ; outer membrane ; PC ; phosphatidylcholine ; PL ; phospholipid ; Papp ; apparent permeability coefficient ; PBS ; phosphate buffered saline ; PMB ; polymyxin B ; POPE ; 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine ; POPG ; 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1&prime ; -rac-glycerol) ; PVPA ; phosph
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 December 2016
• 年：2016
• 卷：243
• 期：Complete
• 页码：214-224
• 全文大小：1482 K
• 卷排序：243

文摘

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.