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Mode of action of teixobactins in cellular membranes

Author

Listed:
  • Rhythm Shukla

    (Utrecht University
    Utrecht University)

  • João Medeiros-Silva

    (Utrecht University)

  • Anish Parmar

    (University of Lincoln
    University of Liverpool
    University of Liverpool)

  • Bram J. A. Vermeulen

    (Utrecht University)

  • Sanjit Das

    (University of Lincoln
    University of Liverpool
    University of Liverpool)

  • Alessandra Lucini Paioni

    (Utrecht University)

  • Shehrazade Jekhmane

    (Utrecht University)

  • Joseph Lorent

    (Utrecht University)

  • Alexandre M. J. J. Bonvin

    (Utrecht University)

  • Marc Baldus

    (Utrecht University)

  • Moreno Lelli

    (University of Florence)

  • Edwin J. A. Veldhuizen

    (Utrecht University)

  • Eefjan Breukink

    (Utrecht University)

  • Ishwar Singh

    (University of Lincoln
    University of Liverpool
    University of Liverpool)

  • Markus Weingarth

    (Utrecht University)

Abstract

The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. The difficult synthesis and unfavourable solubility of teixobactin require modifications, yet insufficient knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill bacteria by binding to cognate cell wall precursors (Lipid II and III). Here we present the binding mode of teixobactins in cellular membranes using solid-state NMR, microscopy, and affinity assays. We solve the structure of the complex formed by an improved teixobactin-analogue and Lipid II and reveal how teixobactins recognize a broad spectrum of targets. Unexpectedly, we find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Our data suggest an additional mechanism affords the excellent activity of teixobactins, which can block the cell wall biosynthesis by capturing precursors in massive clusters on membranes.

Suggested Citation

  • Rhythm Shukla & João Medeiros-Silva & Anish Parmar & Bram J. A. Vermeulen & Sanjit Das & Alessandra Lucini Paioni & Shehrazade Jekhmane & Joseph Lorent & Alexandre M. J. J. Bonvin & Marc Baldus & More, 2020. "Mode of action of teixobactins in cellular membranes," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16600-2
    DOI: 10.1038/s41467-020-16600-2
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    Cited by:

    1. Latinovic, Zoran & Chatterjee, Sharmila C., 2022. "Achieving the promise of AI and ML in delivering economic and relational customer value in B2B," Journal of Business Research, Elsevier, vol. 144(C), pages 966-974.

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