High-resolution experimental and computational electrophysiology reveals weak β-lactam binding events in the porin PorB

Annika Bartsch, Salome Llabres, Florian Pein, Christof Kattner, Markus Schön, Manuel Diehn, Mikio Tanabe, Axel Munk, Ulrich Zachariae (Lead / Corresponding author), Claudia Steinem (Lead / Corresponding author)

Research output: Contribution to journalArticle

50 Downloads (Pure)

Abstract

The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. To design drugs with increased activity against Gram-negative bacteria in the face of the antibiotic resistance crisis, the strict constraints on the physicochemical properties of the permeants imposed by these channels must be better understood. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the β-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis. In particular, an asymmetry often seen in the electrophysiological characteristics of ligand-bound channels is utilised to characterise the binding site and molecular interactions in detail, based on the principles of electro-osmotic flow through the channel. Our results provide a rationale for the determinants that govern the binding and permeation of zwitterionic antibiotics in porin channels.
Original languageEnglish
Article number1264
Pages (from-to)1-11
Number of pages11
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 4 Feb 2019

Fingerprint

Lactams
Porins
Electrophysiology
Anti-Bacterial Agents
Gram-Negative Bacteria
Neisseria meningitidis
Drug Design
Ampicillin
Microbial Drug Resistance
Noise
Binding Sites
Ligands
Bacteria
Membranes

Cite this

Bartsch, Annika ; Llabres, Salome ; Pein, Florian ; Kattner, Christof ; Schön, Markus ; Diehn, Manuel ; Tanabe, Mikio ; Munk, Axel ; Zachariae, Ulrich ; Steinem, Claudia. / High-resolution experimental and computational electrophysiology reveals weak β-lactam binding events in the porin PorB. In: Scientific Reports. 2019 ; Vol. 9. pp. 1-11.
@article{d4206b0373aa4143bb006691bd55810b,
title = "High-resolution experimental and computational electrophysiology reveals weak β-lactam binding events in the porin PorB",
abstract = "The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. To design drugs with increased activity against Gram-negative bacteria in the face of the antibiotic resistance crisis, the strict constraints on the physicochemical properties of the permeants imposed by these channels must be better understood. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the β-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis. In particular, an asymmetry often seen in the electrophysiological characteristics of ligand-bound channels is utilised to characterise the binding site and molecular interactions in detail, based on the principles of electro-osmotic flow through the channel. Our results provide a rationale for the determinants that govern the binding and permeation of zwitterionic antibiotics in porin channels.",
author = "Annika Bartsch and Salome Llabres and Florian Pein and Christof Kattner and Markus Sch{\"o}n and Manuel Diehn and Mikio Tanabe and Axel Munk and Ulrich Zachariae and Claudia Steinem",
note = "Funding: Wellcome Trust Interdisciplinary Research Funds (grant WT097818MF), the Scottish Universities’ Physics Alliance (SUPA) and the Tayside Charitable Trust",
year = "2019",
month = "2",
day = "4",
doi = "10.1038/s41598-018-37066-9",
language = "English",
volume = "9",
pages = "1--11",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

High-resolution experimental and computational electrophysiology reveals weak β-lactam binding events in the porin PorB. / Bartsch, Annika; Llabres, Salome; Pein, Florian; Kattner, Christof; Schön, Markus; Diehn, Manuel; Tanabe, Mikio ; Munk, Axel; Zachariae, Ulrich (Lead / Corresponding author); Steinem, Claudia (Lead / Corresponding author).

In: Scientific Reports, Vol. 9, 1264, 04.02.2019, p. 1-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High-resolution experimental and computational electrophysiology reveals weak β-lactam binding events in the porin PorB

AU - Bartsch, Annika

AU - Llabres, Salome

AU - Pein, Florian

AU - Kattner, Christof

AU - Schön, Markus

AU - Diehn, Manuel

AU - Tanabe, Mikio

AU - Munk, Axel

AU - Zachariae, Ulrich

AU - Steinem, Claudia

N1 - Funding: Wellcome Trust Interdisciplinary Research Funds (grant WT097818MF), the Scottish Universities’ Physics Alliance (SUPA) and the Tayside Charitable Trust

PY - 2019/2/4

Y1 - 2019/2/4

N2 - The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. To design drugs with increased activity against Gram-negative bacteria in the face of the antibiotic resistance crisis, the strict constraints on the physicochemical properties of the permeants imposed by these channels must be better understood. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the β-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis. In particular, an asymmetry often seen in the electrophysiological characteristics of ligand-bound channels is utilised to characterise the binding site and molecular interactions in detail, based on the principles of electro-osmotic flow through the channel. Our results provide a rationale for the determinants that govern the binding and permeation of zwitterionic antibiotics in porin channels.

AB - The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. To design drugs with increased activity against Gram-negative bacteria in the face of the antibiotic resistance crisis, the strict constraints on the physicochemical properties of the permeants imposed by these channels must be better understood. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the β-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis. In particular, an asymmetry often seen in the electrophysiological characteristics of ligand-bound channels is utilised to characterise the binding site and molecular interactions in detail, based on the principles of electro-osmotic flow through the channel. Our results provide a rationale for the determinants that govern the binding and permeation of zwitterionic antibiotics in porin channels.

UR - http://www.scopus.com/inward/record.url?scp=85061058193&partnerID=8YFLogxK

U2 - 10.1038/s41598-018-37066-9

DO - 10.1038/s41598-018-37066-9

M3 - Article

VL - 9

SP - 1

EP - 11

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 1264

ER -