Partitioning of Seven Different Classes of Antibiotics into LPS Monolayers Supports Three Different Permeation Mechanisms through the Outer Bacterial Membrane
Abstract
The outer membrane (OM) of Gram-negative (G-) bacteria presents a barrier for x classes of antibacterial agents. Lipopolysaccharide (LPS), present in the outer leaflet of the OM, is stabilized by divalent cations and is considered to be the major impediment for antibacterial agent permeation. However, the actual affinities of major antibiotic classes toward LPS have not yet been determined. In the present work, we use Langmuir monolayers formed from E. coli Re and Rd types of LPS to record pressure-area isotherms in the presence of antimicrobial agents. Our observations suggest three general types of interactions. Firstly, some antimicrobials demonstrated no measurable interactions with LPS. This lack of interaction in the case of cefsulodin, a third-generation cephalosporin antibiotic, correlates with its low efficacy against G- bacteria. Ampicillin and ciprofloxacin also show no interactions with LPS, but in contrast to cefsulodin, both exhibit good efficacy against G- bacteria, indicating permeation through common porins. Secondly, we observe substantial intercalation of the more hydrophobic antibiotics novobiocin, rifampicin, azithromycin, and telithromycin into relaxed LPS monolayers. These largely re-partition back to the subphase with monolayer compression. We find that the hydrophobic area, charge, and dipole all show correlations with both the mole fraction of antibiotic retainedmore »
- Authors:
-
[2];
[3];
[1]
- Univ. of Maryland, College Park, MD (United States). Biology Dept.
- Univ. of Maryland Baltimore County (UMBC), Baltimore, MD (United States). Dept. of Microbial Pathogenesis
- Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Center for Chemical, Biological, Radiation, and Nuclear Defense and Energy Technology
- Publication Date:
- Research Org.:
- Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program
- OSTI Identifier:
- 1810400
- Report Number(s):
- SAND-2021-2776J
Journal ID: ISSN 0743-7463; 697281
- Grant/Contract Number:
- AC04-94AL85000; NA0003525.
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Langmuir
- Additional Journal Information:
- Journal Volume: 37; Journal Issue: 4; Journal ID: ISSN 0743-7463
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Langmuir monolayers; lipopolysaccharide; LPS, antibiotics; membrane partitioning; lateral pressure; hydrophobic insertion; electrostatic binding
Citation Formats
Cetuk, Hannah, Anishkin, Andriy, Scott, Alison J., Rempe, Susan B., Ernst, Robert K., and Sukharev, Sergei. Partitioning of Seven Different Classes of Antibiotics into LPS Monolayers Supports Three Different Permeation Mechanisms through the Outer Bacterial Membrane. United States: N. p., 2021.
Web. doi:10.1021/acs.langmuir.0c02652.
Cetuk, Hannah, Anishkin, Andriy, Scott, Alison J., Rempe, Susan B., Ernst, Robert K., & Sukharev, Sergei. Partitioning of Seven Different Classes of Antibiotics into LPS Monolayers Supports Three Different Permeation Mechanisms through the Outer Bacterial Membrane. United States. https://doi.org/10.1021/acs.langmuir.0c02652
Cetuk, Hannah, Anishkin, Andriy, Scott, Alison J., Rempe, Susan B., Ernst, Robert K., and Sukharev, Sergei. Fri .
"Partitioning of Seven Different Classes of Antibiotics into LPS Monolayers Supports Three Different Permeation Mechanisms through the Outer Bacterial Membrane". United States. https://doi.org/10.1021/acs.langmuir.0c02652. https://www.osti.gov/servlets/purl/1810400.
@article{osti_1810400,
title = {Partitioning of Seven Different Classes of Antibiotics into LPS Monolayers Supports Three Different Permeation Mechanisms through the Outer Bacterial Membrane},
author = {Cetuk, Hannah and Anishkin, Andriy and Scott, Alison J. and Rempe, Susan B. and Ernst, Robert K. and Sukharev, Sergei},
abstractNote = {The outer membrane (OM) of Gram-negative (G-) bacteria presents a barrier for x classes of antibacterial agents. Lipopolysaccharide (LPS), present in the outer leaflet of the OM, is stabilized by divalent cations and is considered to be the major impediment for antibacterial agent permeation. However, the actual affinities of major antibiotic classes toward LPS have not yet been determined. In the present work, we use Langmuir monolayers formed from E. coli Re and Rd types of LPS to record pressure-area isotherms in the presence of antimicrobial agents. Our observations suggest three general types of interactions. Firstly, some antimicrobials demonstrated no measurable interactions with LPS. This lack of interaction in the case of cefsulodin, a third-generation cephalosporin antibiotic, correlates with its low efficacy against G- bacteria. Ampicillin and ciprofloxacin also show no interactions with LPS, but in contrast to cefsulodin, both exhibit good efficacy against G- bacteria, indicating permeation through common porins. Secondly, we observe substantial intercalation of the more hydrophobic antibiotics novobiocin, rifampicin, azithromycin, and telithromycin into relaxed LPS monolayers. These largely re-partition back to the subphase with monolayer compression. We find that the hydrophobic area, charge, and dipole all show correlations with both the mole fraction of antibiotic retained in the monolayer at the monolayer-bilayer equivalence pressure and the efficacies of these antibiotics against G- bacteria. Thirdly, amine-rich gentamicin and the cationic antimicrobial peptides polymyxin B and colistin show no hydrophobic insertion but are instead strongly driven into the polar LPS layer by electrostatic interactions in a pressure-independent manner. Their intercalation stably increases the area per molecule (by up to 20%), which indicates massive formation of defects in the LPS layer. These defects support a self-promoted permeation mechanism of these antibiotics through the OM, which explains the high efficacy and specificity of these antimicrobials against G- bacteria.},
doi = {10.1021/acs.langmuir.0c02652},
journal = {Langmuir},
number = 4,
volume = 37,
place = {United States},
year = {Fri Jan 15 00:00:00 EST 2021},
month = {Fri Jan 15 00:00:00 EST 2021}
}
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