Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa
Autor: | Bert van den Berg, Matteo Ceccarelli, Richard Wagner, Christian Schleberger, M. Pathania, Tommaso D'Agostino, Igor Bodrenko, Dirk Bumann, Mathias Winterhalter, Silvia Acosta-Gutierrez, Susruta Samanta, Ishan Ghai |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cell Membrane Permeability medicine.drug_class Antibiotics Static Electricity Porins Molecular Dynamics Simulation medicine.disease_cause Crystallography X-Ray 01 natural sciences Ceftazidime Protein Structure Secondary Membrane Potentials 03 medical and health sciences Bacterial Proteins Gram-Negative Bacteria medicine biology 010405 organic chemistry Pseudomonas aeruginosa Chemistry biology.organism_classification 0104 chemical sciences Anti-Bacterial Agents Protein Transport 030104 developmental biology Infectious Diseases Liposomes Biophysics Bacterial outer membrane Bacteria |
Zdroj: | ACS infectious diseases. 4(10) |
ISSN: | 2373-8227 |
Popis: | 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. |
Databáze: | OpenAIRE |
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