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

Graef, F, Richtert, R, Fetz, V, Murgia, X, De Rossi, C, Schneider-Daum, N, Allegretta, G, Elgaher, W, Hauipenthal, J, Empting, M, Beckmann, F, BroEnstrup, M, Hartmann, R, Gordon, S and Lehr, C-M (2018) In Vitro Model of the Gram-Negative Bacterial Cell Envelope for Investigation of Anti-Infective Permeation Kinetics. ACS Infectious Diseases, 4 (8). pp. 1188-1196. ISSN 2373-8227

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Science & Technology; Life Sciences & Biomedicine; Chemistry, Medicinal; Infectious Diseases; Pharmacology & Pharmacy; anti-infectives; drug delivery; drug design; Gram-negative bacterial cell envelope; in vitro model; OUTER-MEMBRANE PERMEABILITY; PSEUDOMONAS-AERUGINOSA; ESCHERICHIA-COLI; DRUG DISCOVERY; BARRIER; PORIN; FLUOROQUINOLONES; ACCUMULATION; RESISTANCE; MOLECULES
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: American Chemical Society
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Date Deposited: 08 Mar 2019 11:40
Last Modified: 11 Mar 2019 04:13
DOI or Identification number: 10.1021/acsinfecdis.7b00165
URI: http://researchonline.ljmu.ac.uk/id/eprint/10276

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