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

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 () and Sebastian Hiller ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33838-0

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