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Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane.
Manioglu, Selen; Modaresi, Seyed Majed; Ritzmann, Noah; Thoma, Johannes; Overall, Sarah A; Harms, Alexander; Upert, Gregory; Luther, Anatol; Barnes, Alexander B; Obrecht, Daniel; Müller, Daniel J; Hiller, Sebastian.
Afiliação
  • Manioglu S; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zürich, Mattenstrasse 26, Basel, Switzerland.
  • Modaresi SM; Biozentrum, University of Basel, Spitalstrasse 41, Basel, Switzerland.
  • Ritzmann N; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zürich, Mattenstrasse 26, Basel, Switzerland.
  • Thoma J; Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden.
  • Overall SA; Laboratory of Physical Chemistry, ETH Zurich, Zurich, Switzerland.
  • Harms A; Biozentrum, University of Basel, Spitalstrasse 41, Basel, Switzerland.
  • Upert G; Spexis AG, Allschwil, Switzerland.
  • Luther A; Bachem AG, Bubendorf, Switzerland.
  • Barnes AB; Laboratory of Physical Chemistry, ETH Zurich, Zurich, Switzerland.
  • Obrecht D; Spexis AG, Allschwil, Switzerland.
  • Müller DJ; Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zürich, Mattenstrasse 26, Basel, Switzerland. daniel.mueller@bsse.ethz.ch.
  • Hiller S; Biozentrum, University of Basel, Spitalstrasse 41, Basel, Switzerland. sebastian.hiller@unibas.ch.
Nat Commun ; 13(1): 6195, 2022 10 21.
Article em En | MEDLINE | ID: mdl-36271003
ABSTRACT
Polymyxins are last-resort antibiotics with potent activity against multi-drug resistant pathogens. They interact with lipopolysaccharide (LPS) in bacterial membranes, but mechanistic details at the molecular level remain unclear. Here, we characterize the interaction of polymyxins with native, LPS-containing outer membrane patches of Escherichia coli by high-resolution atomic force microscopy imaging, along with structural and biochemical assays. We find that polymyxins arrange LPS into hexagonal assemblies to form crystalline structures. Formation of the crystalline structures is correlated with the antibiotic activity, and absent in polymyxin-resistant strains. Crystal lattice parameters alter with variations of the LPS and polymyxin molecules. Quantitative measurements show that the crystalline structures decrease membrane thickness and increase membrane area as well as stiffness. Together, these findings suggest the formation of rigid LPS-polymyxin crystals and subsequent membrane disruption as the mechanism of polymyxin action and provide a benchmark for optimization and de novo design of LPS-targeting antimicrobials.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Polimixinas / Infecções por Escherichia coli Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Polimixinas / Infecções por Escherichia coli Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article