ArticleBiophysical journal2022
Polymyxins induce lipid scrambling and disrupt the homeostasis of Gram-negative bacteria membrane.
Article in Biophysical journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 31 citations in OpenAlex.
- Comparative Effectiveness of Colistin Sodium versus Polymyxin B Sulfate Against CR-GNB: A Retrospective Cohort Study.Infection and drug resistance · 2026Article
- Polymyxins slow down lateral diffusion of proteins and lipopolysaccharide in the E. coli outer membrane.Communications biology · 2025Article
- PmrA Mutations in Drug-ResistantMicroorganisms · 2025Article
- Article
- Bactericidal activity of mammalian histones is caused by large membrane pore formation.Cell reports · 2025Article
- Role of Divalent Ions in Membrane Models of Polymyxin-Sensitive and Resistant Gram-Negative Bacteria.Journal of chemical information and modeling · 2025Article
- Beyond antibiotics: mesenchymal stem cells and bacteriophages-new approaches to combat bacterial resistance in wound infections.Molecular biology reports · 2024Review
- Macromolecular Crowding, Phase Separation, and Homeostasis in the Orchestration of Bacterial Cellular Functions.Chemical reviews · 2024Review
- Photosensitised versus conventional infection control: the local fight continues.Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology · 2024Article
- How Alligator Immune Peptides Kill Gram-Negative Bacteria: A Lipid-Scrambling, Squeezing, and Extracting Mechanism Revealed by Theoretical Simulations.International journal of molecular sciences · 2023Article
- Cyclic lipopeptides as membrane fusion inhibitors against SARS-CoV-2: New tricks for old dogs.Antiviral research · 2023Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polymyxins are increasingly used as the last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, efforts to address the resistance in superbugs are compromised by a poor understanding of the bactericidal modes because high-resolution detection of the cell structure is still lacking. By performing molecular dynamics simulations at a coarse-grained level, here we show that polymyxin B (PmB) disrupts Gram-negative bacterial membranes by altering lipid homeostasis and asymmetry. We found that the binding of PmBs onto the asymmetric outer membrane (OM) loosens the packing of lipopolysaccharides (LPS) and induces unbalanced bending torque between the inner and outer leaflets, which in turn triggers phospholipids to flip from the inner leaflet to the outer leaflet to compensate for the stress deformation. Meanwhile, some LPSs may be detained on the inner membrane (IM). Then, the lipid-scrambled OM undergoes phase separation. Defects are created at the boundaries between LPS-rich domains and phospholipid-rich domains, which consequently facilitate the uptake of PmB across the OM. Finally, PmBs target LPSs detained on the IM and similarly perturb the IM. This lipid Scramble, membrane phase Separation, and peptide Translocation model depicts a novel mechanism by which polymyxins kill bacteria and sheds light on developing a new generation of polymyxins or antibiotic adjuvants with improved killing activities and higher therapeutic indices.
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