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Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation
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    Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation
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    ACS Nano

    Cite this: ACS Nano 2021, 15, 6, 9679–9689
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    https://doi.org/10.1021/acsnano.1c00218
    Published April 22, 2021
    Copyright © 2021 American Chemical Society

    Abstract

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    Disruption of cell membranes is a fundamental host defense response found in virtually all forms of life. The molecular mechanisms vary but generally lead to energetically favored circular nanopores. Here, we report an elaborate fractal rupture pattern induced by a single side-chain mutation in ultrashort (8–11-mers) helical peptides, which otherwise form transmembrane pores. In contrast to known mechanisms, this mode of membrane disruption is restricted to the upper leaflet of the bilayer where it exhibits propagating fronts of peptide-lipid interfaces that are strikingly similar to viscous instabilities in fluid flow. The two distinct disruption modes, pores and fractal patterns, are both strongly antimicrobial, but only the fractal rupture is nonhemolytic. The results offer wide implications for elucidating differential membrane targeting phenomena defined at the nanoscale.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.1c00218.

    • Table summarizing biological activities of the peptides and antibiotics used in this study; RP-HPLC traces and MALDI-ToF spectra for the peptides; MD simulations for the peptides and their insertion modes in membranes; CD and ITC spectra for peptide folding and thermodynamics in membranes; and AFM images of SLBs and microfluidics data for GUVs and live bacteria (PDF)

    • Growth dynamics in fractal ruptures (AVI)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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    This article is cited by 17 publications.

    1. Alex Hoose, Javier Garcia-Ruiz, Corrin Blake, Ciara C. M. Lally, Andrea Briones, Bart W. Hoogenboom, Christian D. Lorenz, Maxim G. Ryadnov. Multimodal Membrane Poration by Thanatin. Langmuir 2025, Article ASAP.
    2. James E. Noble, Paula Vila-Gómez, Stephanie Rey, Camilla Dondi, Andrea Briones, Purnank Aggarwal, Alex Hoose, Maryana Baran, Maxim G. Ryadnov. Folding-Mediated DNA Delivery by α-Helical Amphipathic Peptides. ACS Biomaterials Science & Engineering 2023, 9 (5) , 2584-2595. https://doi.org/10.1021/acsbiomaterials.3c00221
    3. Arpita Roy, Nirod Kumar Sarangi, Surajit Ghosh, Amrutha Prabhakaran, Tia E. Keyes. Leaflet by Leaflet Synergistic Effects of Antimicrobial Peptides on Bacterial and Mammalian Membrane Models. The Journal of Physical Chemistry Letters 2023, 14 (16) , 3920-3928. https://doi.org/10.1021/acs.jpclett.3c00119
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    7. Isabel D. Bennett, Jonathan R. Burns, Maxim G. Ryadnov, Stefan Howorka, Alice L. B. Pyne. Lipidated DNA Nanostructures Target and Rupture Bacterial Membranes. Small 2024, 20 (35) https://doi.org/10.1002/smll.202207585
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    9. Xiao Zhang, Yachao Li, Yuying Yang, Kefurong Deng, Rongyan Liu, Ruigang Hou, Xianghui Xu. Molecular and supramolecular engineering on lipopeptide-based hole-punching nanotoxins to trigger multimodal death of drug-resistant tumors: Apoptosis, necrosis and autophagy. Chemical Engineering Journal 2023, 465 , 142698. https://doi.org/10.1016/j.cej.2023.142698
    10. Yuewen Zhang, Ibolya Kepiro, Maxim G. Ryadnov, Stefano Pagliara, . Single Cell Killing Kinetics Differentiate Phenotypic Bacterial Responses to Different Antibacterial Classes. Microbiology Spectrum 2023, 11 (1) https://doi.org/10.1128/spectrum.03667-22
    11. Alberto Gubbiotti, Matteo Baldelli, Giovanni Di Muccio, Paolo Malgaretti, Sophie Marbach, Mauro Chinappi. Electroosmosis in nanopores: computational methods and technological applications. Advances in Physics: X 2022, 7 (1) https://doi.org/10.1080/23746149.2022.2036638
    12. Javier Garcia-Ruiz, Maxim G. Ryadnov. DANAMIC: Data analyzer of minimum inhibitory concentrations – Protocol to analyze antimicrobial susceptibility data. STAR Protocols 2022, 3 (4) , 101782. https://doi.org/10.1016/j.xpro.2022.101782
    13. Jehangir Cama, Kareem Al Nahas, Marcus Fletcher, Katharine Hammond, Maxim G. Ryadnov, Ulrich F. Keyser, Stefano Pagliara. An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics. Scientific Reports 2022, 12 (1) https://doi.org/10.1038/s41598-022-07973-z
    14. Urszula Łapińska, Margaritis Voliotis, Ka Kiu Lee, Adrian Campey, M Rhia L Stone, Brandon Tuck, Wanida Phetsang, Bing Zhang, Krasimira Tsaneva-Atanasova, Mark AT Blaskovich, Stefano Pagliara. Fast bacterial growth reduces antibiotic accumulation and efficacy. eLife 2022, 11 https://doi.org/10.7554/eLife.74062
    15. Andrea Hornemann, Diane M. Eichert, Arne Hoehl, Brigitte Tiersch, Gerhard Ulm, Maxim G. Ryadnov, Burkhard Beckhoff. Investigating Membrane‐Mediated Antimicrobial Peptide Interactions with Synchrotron Radiation Far‐Infrared Spectroscopy. ChemPhysChem 2022, 23 (4) https://doi.org/10.1002/cphc.202100815
    16. Patrick B. Timmons, Chandralal M. Hewage. Conformation and membrane interaction studies of the potent antimicrobial and anticancer peptide palustrin-Ca. Scientific Reports 2021, 11 (1) https://doi.org/10.1038/s41598-021-01769-3
    17. Urszula Łapińska, Margaritis Voliotis, Ka Kiu Lee, Adrian Campey, M. Rhia L. Stone, Wanida Phetsang, Bing Zhang, Krasimira Tsaneva-Atanasova, Mark A. T. Blaskovich, Stefano Pagliara. Fast bacterial growth reduces antibiotic accumulation and efficacy. 2021https://doi.org/10.1101/2021.10.18.464851
    18. Jehangir Cama, Kareem Al Nahas, Marcus Fletcher, Katharine Hammond, Maxim G. Ryadnov, Ulrich F. Keyser, Stefano Pagliara. An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics. 2021https://doi.org/10.1101/2021.09.08.459503
    19. Kareem Al Nahas, Ulrich F. Keyser. Standardizing characterization of membrane active peptides with microfluidics. Biomicrofluidics 2021, 15 (4) https://doi.org/10.1063/5.0048906

    ACS Nano

    Cite this: ACS Nano 2021, 15, 6, 9679–9689
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.1c00218
    Published April 22, 2021
    Copyright © 2021 American Chemical Society

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