Outer membrane permeability and antibiotic resistance

Abstract

To date most antibiotics are targeted at intracellular processes, and must be able to penetrate the bacterial cell envelope. In particular, the outer membrane of gram-negative bacteria provides a formidable barrier that must be overcome. There are essentially two pathways that antibiotics can take through the outer membrane: a lipid-mediated pathway for hydrophobic antibiotics, and general diffusion porins for hydrophilic antibiotics. The lipid and protein compositions of the outer membrane have a strong impact on the sensitivity of bacteria to many types of antibiotics, and drug resistance involving modifications of these macromolecules is common. This review will describe the molecular mechanisms for permeation of antibiotics through the outer membrane, and the strategies that bacteria have deployed to resist antibiotics by modifications of these pathways.

Figure 1

Overall organization of LPS and structure of Kdo₂-Lipid A. The left hand side shows the organization of LPS in 3 regions: Lipid A, core oligosaccharide (itself subdivided into inner core and outer core), and O-antigen. Abbreviations are: Kdo, 3-deoxy-D-manno-oct-2-ulosonic acid; Hep, L-glycero-D-manno-heptose; Glc, D-glucose; Gal, D-galactose; R, a variety of different substituents (see reference for details). The right hand side shows the structure of Kdo2-Lipid A, the minimal entity required for E. coli growth.

Figure 2

Structure of an OmpF monomer. A) Side view of a single β-barrel of the OmpF trimer to highlight the location of the protein in the membrane bilayer (“EC” refers to the extracellular side, and “Peri” refers to the periplasmic side); note that some of the protein structure has been cut out of view in order to better visualize the constricting L3 loop (orange). B) View of the OmpF monomer from the periplasmic side, highlighting the configuration of the eyelet or constriction zone. Important residues of the eyelet are acidic residues of the L3 loop (in red) and a cluster of basic amino acids of the opposite barrel wall (in blue).

Figure 3

Docking of an ampicillin molecule at the constriction zone of an OmpF monomer. The top panel shows the fit of the ampicillin molecule within the pore, with the carboxylate group attracted to the cluster of arginines in the OmpF barrel, and the ammonium group close to the acidic L3 loop residues. Colors of atoms in ampicillin are as follows: green for carbon, red for oxygen, blue for nitrogen and yellow for sulfur. Hydrogen atoms are not shown. The OmpF backbone is shown as a yellow ribbon. The lower panel shows the solvent accessible surface of the OmpF eyelet highlighting the electrostatic potential with blue color for positive potential and red color for negative potentials. Ampicillin is shown in a stick model with the following colors: white for carbon, red for oxygen, blue for nitrogen, green for sulfur and violet for hydrogen. Reproduced from reference with permission (copyright © 1993–2008 by The National Academy of Sciences of the United States of America, all rights reserved).