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Assessing Barriers for Antimicrobial Penetration in Complex Asymmetric Bacterial Membranes: A Case Study with Thymol

Sharma, P and Parthasarathi, S and Patil, N and Waskar, M and Raut, JS and Puranik, M and Ayappa, KG and Basu, JK (2020) Assessing Barriers for Antimicrobial Penetration in Complex Asymmetric Bacterial Membranes: A Case Study with Thymol. In: Langmuir, 36 (30). pp. 8800-8814.

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Official URL: https://doi.org/10.1021/acs.langmuir.0c01124


The bacterial cell envelope is a complex multilayered structure evolved to protect bacteria in hostile environments. An understanding of the molecular basis for the interaction and transport of antibacterial therapeutics with the bacterial cell envelope will enable the development of drug molecules to combat bacterial infections and suppress the emergence of drug-resistant strains. Here we report the successful creation of an in vitro supported lipid bilayer (SLB) platform of the outer membrane (OM) of E. coli, an archetypical Gram-negative bacterium, containing the full smooth lipopolysaccharide (S-LPS) architecture of the membrane. Using this platform, we performed fluorescence correlation spectroscopy (FCS) in combination with molecular dynamics (MD) simulations to measure lipid diffusivities and provide molecular insights into the transport of natural antimicrobial agent thymol. Lipid diffusivities measured on symmetric supported lipid bilayers made up of inner membrane lipids show a distinct increase in the presence of thymol as also corroborated by MD simulations. However, lipid diffusivities in the asymmetric OM consisting of only S-LPS are invariant upon exposure to thymol. Increasing the phospholipid content in the LPS-containing outer leaflet improved the penetration toward thymol as reflected in slightly higher relative diffusivity changes in the inner leaflet when compared with the outer leaflet. Free-energy computations reveal the presence of a barrier (∼6 kT) only in the core-saccharide region of the OM for the translocation of thymol while the external O-antigen part is easily traversed. In contrast, thymol spontaneously inserts into the inner membrane. In addition to providing leaflet-resolved penetration barriers in bacterial membranes, we also assess the ability of small molecules to penetrate various membrane components. With rising bacterial resistance, our study opens up the possibility of screening potential antimicrobial drug candidates using these realistic model platforms for Gram-negative bacteria.

Item Type: Journal Article
Publication: Langmuir
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to American Chemical Society.
Keywords: Antimicrobial agents; Diffusion; Escherichia coli; Fluorescence spectroscopy; Free energy; Lipid bilayers; Molecular dynamics; Molecules; Phospholipids; Spectroscopic analysis, Drug-resistant strains; Fluorescence Correlation Spectroscopy; Free energy computations; Molecular dynamics simulations; Multi-layered structure; Natural-antimicrobials; Supported lipid bilayer (SLB); Supported lipid bilayers, Phenols
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Division of Mechanical Sciences > Chemical Engineering
Division of Physical & Mathematical Sciences > Physics
Date Deposited: 15 Feb 2023 11:21
Last Modified: 15 Feb 2023 11:21
URI: https://eprints.iisc.ac.in/id/eprint/80260

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