id8b00149_si_001.pdf (3.86 MB)
Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa
journal contribution
posted on 2018-07-24, 00:00 authored by Susruta Samanta, Igor Bodrenko, Silvia Acosta-Gutiérrez, Tommaso D’Agostino, Monisha Pathania, Ishan Ghai, Christian Schleberger, Dirk Bumann, Richard Wagner, Mathias Winterhalter, Bert van den Berg, Matteo CeccarelliUnderstanding 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.