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Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane

Author

Listed:
  • Selen Manioglu

    (Eidgenössische Technische Hochschule (ETH) Zürich)

  • Seyed Majed Modaresi

    (University of Basel)

  • Noah Ritzmann

    (Eidgenössische Technische Hochschule (ETH) Zürich)

  • Johannes Thoma

    (University of Gothenburg)

  • Sarah A. Overall

    (Laboratory of Physical Chemistry, ETH Zurich)

  • Alexander Harms

    (University of Basel)

  • Gregory Upert

    (Spexis AG)

  • Anatol Luther

    (Bachem AG)

  • Alexander B. Barnes

    (Laboratory of Physical Chemistry, ETH Zurich)

  • Daniel Obrecht

    (Spexis AG)

  • Daniel J. Müller

    (Eidgenössische Technische Hochschule (ETH) Zürich)

  • Sebastian Hiller

    (University of Basel)

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.

Suggested Citation

  • Selen Manioglu & Seyed Majed Modaresi & Noah Ritzmann & Johannes Thoma & Sarah A. Overall & Alexander Harms & Gregory Upert & Anatol Luther & Alexander B. Barnes & Daniel Obrecht & Daniel J. Müller & , 2022. "Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33838-0
    DOI: 10.1038/s41467-022-33838-0
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    Cited by:

    1. Telmo O. Paiva & Albertus Viljoen & Yves F. Dufrêne, 2022. "Seeing the unseen: High-resolution AFM imaging captures antibiotic action in bacterial membranes," Nature Communications, Nature, vol. 13(1), pages 1-3, December.
    2. Adéla Melcrová & Sourav Maity & Josef Melcr & Niels A. W. Kok & Mariella Gabler & Jonne Eyden & Wenche Stensen & John S. M. Svendsen & Arnold J. M. Driessen & Siewert J. Marrink & Wouter H. Roos, 2023. "Lateral membrane organization as target of an antimicrobial peptidomimetic compound," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Selen Manioglu & Seyed Majed Modaresi & Johannes Thoma & Sarah A. Overall & Gregory Upert & Anatol Luther & Alexander B. Barnes & Daniel Obrecht & Daniel J. Müller & Sebastian Hiller, 2023. "Reply to: Antibiotics and hexagonal order in the bacterial outer membrane," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    4. Kerry R. Buchholz & Mike Reichelt & Matthew C. Johnson & Sarah J. Robinson & Peter A. Smith & Steven T. Rutherford & John G. Quinn, 2024. "Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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