![]() Under stress, pathogenic serotypes of Salmonella enterica remodel their LPSs through the PhoPQ two-component regulatory system that increases resistance to both conventional antibiotics and antimicrobial peptides (AMPs). Gram-negative bacteria are protected from their environment by an outer membrane that is primarily composed of lipopolysaccharides (LPSs). Resource Type: Journal Article: 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 = , ![]() (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. Publication Date: Research Org.: Sandia National Lab. Center for Chemical, Biological, Radiation, and Nuclear Defense and Energy Technology (SNL-NM), Albuquerque, NM (United States). of Maryland Baltimore County (UMBC), Baltimore, MD (United States). of Maryland, College Park, MD (United States). 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. Their intercalation stably increases the area per molecule (by up to 20%), which indicates massive formation of defects in the LPS layer. 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. We find that the hydrophobic area, charge, and dipole all show correlations with both the mole fraction of antibiotic retained more ยป in the monolayer at the monolayer-bilayer equivalence pressure and the efficacies of these antibiotics against G- bacteria. These largely re-partition back to the subphase with monolayer compression. Secondly, we observe substantial intercalation of the more hydrophobic antibiotics novobiocin, rifampicin, azithromycin, and telithromycin into relaxed LPS monolayers. 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. This lack of interaction in the case of cefsulodin, a third-generation cephalosporin antibiotic, correlates with its low efficacy against G- bacteria. Firstly, some antimicrobials demonstrated no measurable interactions with LPS. Our observations suggest three general types of interactions. coli Re and Rd types of LPS to record pressure-area isotherms in the presence of antimicrobial agents. In the present work, we use Langmuir monolayers formed from E. However, the actual affinities of major antibiotic classes toward LPS have not yet been determined. 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. The outer membrane (OM) of Gram-negative (G-) bacteria presents a barrier for x classes of antibacterial agents.
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