Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa

Samanta, Susruta and Bodrenko, Igor and Acosta-Gutiérrez, Silvia and D'Agostino, Tommaso and Pathania, Monisha and Ghai, Ishan and Schleberger, Christian and Bumann, Dirk and Wagner, Richard and Winterhalter, Mathias and van den Berg, Bert and Ceccarelli, Matteo. (2018) Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa. ACS infectious diseases, 4 (10). pp. 1519-1528.

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Official URL: https://edoc.unibas.ch/65220/

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Understanding molecular properties of outer membrane channels of Gram-negative bacteria is of fundamental significance as they are the entry point of polar antibiotics into bacteria. Outer membrane proteomics revealed OccK8 (OprE) to be among the five most expressed substrate specific channels of the clinically important Pseudomonas aeruginosa. The high-resolution X-ray structure and electrophysiology highlighted a very narrow pore. However, experimental in vitro methods showed the transport of natural amino acids and antibiotics, among them ceftazidime. We used molecular dynamics simulations to reveal the importance of the physicochemical properties of ceftazidime in modulating the translocation through OccK8, proposing a structure-function relationship. As in general porins, the internal electric field favors the translocation of polar molecules by gainful energy compensation in the central constriction region. Importantly, the comparatively narrow OccK8 pore can undergo a substrate-induced expansion to accommodate relatively large-sized substrates.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Infection Biology > Molecular Microbiology (Bumann)
UniBasel Contributors:Bumann, Dirk and Schleberger, Christian
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Apr 2020 21:31
Deposited On:26 Apr 2020 21:31

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