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Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A

Author

Listed:
  • Kerry R. Buchholz

    (Genentech, Inc.)

  • Mike Reichelt

    (Genentech, Inc.)

  • Matthew C. Johnson

    (Genentech, Inc.)

  • Sarah J. Robinson

    (Genentech, Inc.)

  • Peter A. Smith

    (Genentech, Inc.
    Inc.)

  • Steven T. Rutherford

    (Genentech, Inc.)

  • John G. Quinn

    (Genentech, Inc.)

Abstract

Polymyxins are gram-negative antibiotics that target lipid A, the conserved membrane anchor of lipopolysaccharide in the outer membrane. Despite their clinical importance, the molecular mechanisms underpinning polymyxin activity remain unresolved. Here, we use surface plasmon resonance to kinetically interrogate interactions between polymyxins and lipid A and derive a phenomenological model. Our analyses suggest a lipid A-catalyzed, three-state mechanism for polymyxins: transient binding, membrane insertion, and super-stoichiometric cluster accumulation with a long residence time. Accumulation also occurs for brevicidine, another lipid A-targeting antibacterial molecule. Lipid A modifications that impart polymyxin resistance and a non-bactericidal polymyxin derivative exhibit binding that does not evolve into long-lived species. We propose that transient binding to lipid A permeabilizes the outer membrane and cluster accumulation enables the bactericidal activity of polymyxins. These findings could establish a blueprint for discovery of lipid A-targeting antibiotics and provide a generalizable approach to study interactions with the gram-negative outer membrane.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49200-5
    DOI: 10.1038/s41467-024-49200-5
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    References listed on IDEAS

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    1. Enrique R. Rojas & Gabriel Billings & Pascal D. Odermatt & George K. Auer & Lillian Zhu & Amanda Miguel & Fred Chang & Douglas B. Weibel & Julie A. Theriot & Kerwyn Casey Huang, 2018. "The outer membrane is an essential load-bearing element in Gram-negative bacteria," Nature, Nature, vol. 559(7715), pages 617-621, July.
    2. Craig R. MacNair & Jonathan M. Stokes & Lindsey A. Carfrae & Aline A. Fiebig-Comyn & Brian K. Coombes & Michael R. Mulvey & Eric D. Brown, 2018. "Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    3. Yong-Xin Li & Zheng Zhong & Wei-Peng Zhang & Pei-Yuan Qian, 2018. "Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    4. 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.
    5. Kade D. Roberts & Yan Zhu & Mohammad A. K. Azad & Mei-Ling Han & Jiping Wang & Lynn Wang & Heidi H. Yu & Andrew S. Horne & Jo-Anne Pinson & David Rudd & Nicolas H. Voelcker & Nitin A. Patil & Jinxin Z, 2022. "A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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