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 physico-chemical 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.

Getting drugs through small pores: Exploiting the porins pathway in Pseudomonas aeruginosa

Susruta Samanta;Igor Bodrenko
Co-primo
;
Silvia Acosta-Gutieŕrez;Tommaso D’Agostino;Mathias Winterhalter;Matteo Ceccarelli
Ultimo
2018-01-01

Abstract

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 physico-chemical 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.
Antibiotics transport; Crystal structure; Molecular simulations; Outer membrane; Porins; Infectious diseases
File in questo prodotto:
File Dimensione Formato  
ACS Infect. Dis. 2018 Samanta.pdf

Solo gestori archivio

Tipologia: versione editoriale
Dimensione 4.43 MB
Formato Adobe PDF
4.43 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/253091
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 15
social impact