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  • Review Article
  • Published:

The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria

Nature Reviews Microbiology volume 6, pages 893–903 (2008)Cite this article

Key Points

  • Porin modification is a major bacterial resistance strategy that restricts the influx of β-lactam and fluoroquinolone antibiotics.

  • Clinical multidrug resistant enterobacterial isolates that exhibit modified membrane permeability are highly prevalent.

  • Interactions between antibiotic molecules and porin channels govern translocation efficiency.

  • New physico-chemical techniques are being developed to assess drug–channel interactions and to quantify translocation through porins.

  • Computer modelling of the pathway of substrates through porins provides information on the orientation and interaction of substrates in the channel.

  • Quantification of antibiotic translocation provides new insights into how to optimize drug molecules so that they have sufficient permeation rates to circumvent multidrug resistance mechanisms.

Abstract

Gram-negative bacteria are responsible for a large proportion of antibiotic-resistant bacterial diseases. These bacteria have a complex cell envelope that comprises an outer membrane and an inner membrane that delimit the periplasm. The outer membrane contains various protein channels, called porins, which are involved in the influx of various compounds, including several classes of antibiotics. Bacterial adaptation to reduce influx through porins is an increasing problem worldwide that contributes, together with efflux systems, to the emergence and dissemination of antibiotic resistance. An exciting challenge is to decipher the genetic and molecular basis of membrane impermeability as a bacterial resistance mechanism. This Review outlines the bacterial response towards antibiotic stress on altered membrane permeability and discusses recent advances in molecular approaches that are improving our knowledge of the physico-chemical parameters that govern the translocation of antibiotics through porin channels.

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Figure 1: Multidrug resistance mechanisms associated with porin modification.
Figure 2: Liposome swelling assay.
Figure 3: Antibiotic docking to porin channels.

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Acknowledgements

Support for this project was obtained through European Union grant MRTN-CT-2005–019335 “Translocation”, COST Action BM0701 “ATENS” and from the Université de la Méditerranée and Service de Santé des Armées.

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  1. UMR-MD-1, Transporteurs Membranaires, Chimiorésistance et Drug-Design, Facultés de Médecine et de harmacie, Université de la Méditerranée, 13385, Marseille, France

    Jean-Marie Pagès & Chloë E. James

  2. School of Engineering and Science, Jacobs University Bremen, 28759, Bremen, Germany

    Mathias Winterhalter

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DATABASES

Entrez Genome Project

Acinetobacter baumannii

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Neisseria gonorrhoeae

Pseudomonas aeruginosa

S. typhi

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Transport Protein Database

Glossary

Nosocomial

Hospital-acquired infection.

Conductance

A measure of translocated charges per unit time and voltage gradient.

Selectivity

The translocation efficiency of a channel for a particular type of ion with respect to another ion.

Voltage gating

Effect observed for some channels whereby a high voltage gradient causes a sudden closure of the ion current. The molecular origins remain unsolved.

β-lactam

A major family of antibiotic molecules.

Antibiotherapy

A therapy that uses antibiotics to treat infections.

Cephalosporins and carbapenems

Two subclasses of the β-lactam family.

Bacteraemia

A medical condition in which bacteria enter the bloodstream.

Permeation

Diffusion through a membrane, either through the lipid or through channels or carriers.

Metadynamics modelling

A method to simulate rare events on the basis of the choice of the relevant variables of a process and on the acceleration of these variables.

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Pagès, JM., James, C. & Winterhalter, M. The porin and the permeating antibiotic: a selective diffusion barrier in Gram-negative bacteria. Nat Rev Microbiol 6, 893–903 (2008). https://doi.org/10.1038/nrmicro1994

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