期刊
LANGMUIR
卷 37, 期 4, 页码 1372-1385出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.langmuir.0c02652
关键词
-
资金
- Sandia's Laboratory Directed Research and Development program
- U.S. Department of Energy's National Nuclear Security Administration [DE-NA0003525]
The study found that different types of antimicrobial agents interact with LPS in the outer membrane of bacteria in different ways, including no interaction, hydrophobic insertion, and electrostatically driven insertion. Specifically, the hydrophobic antibiotics showed substantial intercalation into relaxed LPS monolayers, while amine-rich and cationic antimicrobial agents were driven into the polar LPS layer by electrostatic interactions, increasing the area per molecule and supporting a self-promoted permeation mechanism through the outer membrane.
The outer membrane (OM) of Gram-negative (G-) bacteria presents a barrier for many 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. First, 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. Second, we observe substantial intercalation of the more hydrophobic antibiotics, novobiocin, rifampicin, azithromycin, and telithromycin, into relaxed LPS monolayers. These largely repartition 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. Third, 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.
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