ArticleComputational and structural biotechnology journal2021
Coarse-grained simulations uncover Gram-negative bacterial defense against polymyxins by the outer membrane.
Article in Computational and structural biotechnology journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 25 citations in OpenAlex.
- Antimicrobial Peptide Activity in Lipid Bilayers with Smooth-Type Lipopolysaccharides.Analytical chemistry · 2026Article
- Polymyxins slow down lateral diffusion of proteins and lipopolysaccharide in the E. coli outer membrane.Communications biology · 2025Article
- Retargeting Gram-Positive-Only Adarotene-Derived Antibacterials to Broad-Spectrum Antibiotics.Antibiotics (Basel, Switzerland) · 2025Article
- Role of Divalent Ions in Membrane Models of Polymyxin-Sensitive and Resistant Gram-Negative Bacteria.Journal of chemical information and modeling · 2025Article
- Depth-Resolved Temperature-Dependent Penetration of Polymyxin B in Phospholipids/Lipopolysaccharide Asymmetric Bilayers.ACS omega · 2025Article
- Seeing is believing: Illuminating the Gram-negative outer membrane with molecular dynamics simulations.Current opinion in structural biology · 2024Review
- Molecular dynamics simulation on regulation of liquid-liquid phase separation of repetitive peptides.Scientific reports · 2024Article
- Cell cycle dependent coordination of surface layer biogenesis in Caulobacter crescentus.Nature communications · 2024Article
- Insights into colistin-mediated fluorescence labelling of bacterial LPS.RSC advances · 2024Article
- Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption.ACS infectious diseases · 2022Article
- Review
- Polymyxin B1 within theBiophysical reviews · 2021Review
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The outer membrane (OM) of Gram-negative bacteria is a formidable barrier against antibiotics. Understanding the structure and function of the OM is essential for the discovery of novel membrane-acting agents against multidrug-resistant Gram-negative pathogens. However, it remains challenging to obtain three-dimensional structure of bacterial membranes using crystallographic approaches, which has significantly hindered the elucidation of its interaction with antibiotics. Here, we developed an asymmetric OM model consisting of rough lipopolysaccharide (LPS) and three key types of phospholipids. Using coarse-grained molecular dynamics simulations, we investigated the interaction dynamics of LPS-containing OM with the polymyxins, a last-line class of antibiotics against Gram-negative 'superbugs'. We discovered that polymyxin molecules spontaneously penetrated the OM core sugar region where most were trapped before entering the lipid A region. Examination of the free energy profile of polymyxin penetration revealed a major free energy barrier at the LPS inner core and lipid A interface. Further analysis revealed calcium ions predominantly distributed in the inner core region and mediated extensive cross-linking interactions between LPS molecules, thereby inhibiting the penetration of polymyxins into the hydrophobic region of the OM. Collectively, our results provide novel mechanistic insights into an intrinsic defense of Gram-negative bacteria to polymyxins and may help identify new antimicrobial targets.
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