ArticleThe Journal of antimicrobial chemotherapy2020
Molecular dynamics simulations informed by membrane lipidomics reveal the structure-interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii.
Article in The Journal of antimicrobial chemotherapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 47 citations in OpenAlex.
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- Molecular dynamics simulations of proteins: an in-depth review of computational strategies, structural insights, and their role in medicinal chemistry and drug development.Biological cybernetics · 2025Review
- Retargeting Gram-Positive-Only Adarotene-Derived Antibacterials to Broad-Spectrum Antibiotics.Antibiotics (Basel, Switzerland) · 2025Article
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- A novel small RNA PhaS contributes to polymyxin B-heteroresistance in carbapenem-resistantEmerging microbes & infections · 2024Article
- OXA β-lactamases frombioRxiv : the preprint server for biology · 2024Article
- Seeing is believing: Illuminating the Gram-negative outer membrane with molecular dynamics simulations.Current opinion in structural biology · 2024Review
- Enhanced Sampling Molecular Dynamics Simulations Reveal Transport Mechanism of Glycoconjugate Drugs through GLUT1.International journal of molecular sciences · 2024Article
- Insights into colistin-mediated fluorescence labelling of bacterial LPS.RSC advances · 2024Article
- Structure-Interaction Relationship of Polymyxins with Lung Surfactant.Journal of medicinal chemistry · 2023Article
- Genomics analysis of KPC-2 and NDM-5-producing Enterobacteriaceae in migratory birds from Qinghai Lake, China.Applied microbiology and biotechnology · 2023Article
- Model-informed dose optimisation of polymyxin-rifampicin combination therapy against multidrug-resistant Acinetobacter baumannii.International journal of antimicrobial agents · 2023Article
- Size-Controlled Ammonium-Based Homopolymers as Broad-Spectrum Antibacterials.Antibiotics (Basel, Switzerland) · 2023Article
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Authors and funding
14 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundMDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level.
methodsWe constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure-interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM.
resultsPolymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space.
conclusionsThe thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure-interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.
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