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ACS Infect Dis. 2018 Aug 10;4(8):1188-1196. doi: 10.1021/acsinfecdis.7b00165. Epub 2018 May 24.

In Vitro Model of the Gram-Negative Bacterial Cell Envelope for Investigation of Anti-Infective Permeation Kinetics.

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Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI) , Saarland University , Campus Building E8 1 , 66123 Saarbrücken , Germany.
Department of Pharmacy , Saarland University , Campus Building E8 1 , 66123 Saarbrücken , Germany.
Department of Chemical Biology, HZI , German Center for Infection Research , Inhoffenstraße 7 , 38124 Braunschweig , Germany.
School of Engineering and Science , Jacobs University Bremen , Campus Ring 1 , 28759 Bremen , Germany.
Department of Drug Design and Optimization, HIPS, HZI , Saarland University , Campus Building E8 1 , 66123 Saarbrücken , Germany.
Institute of Materials Research , Helmholtz-Zentrum Geesthacht , Max-Planck-Straße 1 , 21502 Geesthacht , Germany.
School of Pharmacy and Biomolecular Sciences , Liverpool John Moores University , James Parsons Building, Byrom Street , L3 3AF Liverpool , United Kingdom.


The cell envelope of Gram-negative bacteria is a formidable biological barrier, inhibiting the action of antibiotics by impeding their permeation into the intracellular environment. In-depth understanding of permeation through this barrier remains a challenge, despite its critical role in antibiotic activity. We therefore designed a divisible in vitro permeation model of the Gram-negative bacterial cell envelope, mimicking its three essential structural elements, the inner membrane and the periplasmic space as well as the outer membrane, on a Transwell setup. The model was characterized by contemporary imaging techniques and employed to generate reproducible quantitative and time-resolved permeation data for various fluorescent probes and anti-infective molecules of different structure and physicochemical properties. For a set of three fluorescent probes, the permeation through the overall membrane model was found to correlate with in bacterio permeation. Even more interestingly, for a set of six Pseudomonas quorum sensing inhibitors, such permeability data were found to be predictive for their corresponding in bacterio activities. Further exploration of the capabilities of the overall model yielded a correlation between the permeability of porin-independent antibiotics and published in bacterio accumulation data; a promising ability to provide structure-permeability information was also demonstrated. Such a model may therefore constitute a valuable tool for the development of novel anti-infective drugs.


Gram-negative bacterial cell envelope; anti-infectives; drug delivery; drug design; in vitro model

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