Understanding Carbapenem Translocation through OccD3 (OpdP) of Pseudomonas aeruginosa

Pseudomonas aeruginosa utilizes a plethora of substrate specific channels for the uptake of small nutrients. OccD3 (OpdP or PA4501) is an OprD-like arginine uptake channel of P. aeruginosa whose role has been implicated in carbapenem uptake. To understand the mechanism of selective permeation, we re...

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Bibliographic Details
Published in:ACS chemical biology 2017-06, Vol.12 (6), p.1656-1664
Main Authors: Soundararajan, Gowrishankar, Bhamidimarri, Satya Prathyusha, Winterhalter, Mathias
Format: Article
Language:English
Subjects:
Bacterial Proteins - metabolism
Binding Sites
Carbapenems - pharmacokinetics
Imipenem - pharmacokinetics
Ion Channels - metabolism
Lipid Bilayers - metabolism
Membranes, Artificial
Mutagenesis, Site-Directed
Pseudomonas aeruginosa - metabolism
Substrate Specificity
Thienamycins - pharmacokinetics
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Summary:Pseudomonas aeruginosa utilizes a plethora of substrate specific channels for the uptake of small nutrients. OccD3 (OpdP or PA4501) is an OprD-like arginine uptake channel of P. aeruginosa whose role has been implicated in carbapenem uptake. To understand the mechanism of selective permeation, we reconstituted single OccD3 channels in a planar lipid bilayer and characterized the interaction with Imipenem and Meropenem, analyzing the ion current fluctuation in the presence of substrates. We performed point mutations in the constriction region of OccD3 to understand the binding and translocation of antibiotic in OccD3. By mutating two key residues in the substrate binding sites of OccD3 (located in the internal loop L7 and basic ladder), we emphasize the importance of these residues. We show that carbapenem antibiotics follow a similar path as arginine through the constriction zone and the basic ladder to translocate across OccD3.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.6b01150