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Structural studies suggest aggregation as one of the modes of action for teixobactin

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Abstract

Teixobactin is a new promising antibiotic that targets cell wall biosynthesis by binding to lipid II and has no detectable resistance thanks to its unique but yet not fully understood mechanism of operation. To aid in the structure-based design of teixobactin analogues with improved pharmacological properties, we present a 3D structure of native teixobactin in membrane mimetics and characterise its binding to lipid II through a combination of solution NMR and fast (90 kHz) magic angle spinning solid state NMR. In NMR titrations, we observe a pattern strongly suggesting interactions between the backbone of the C-terminal “cage” and the pyrophosphate moiety in lipid II. We find that the N-terminal part of teixobactin does not only act as a membrane anchor, as previously thought, but is actively involved in binding. Moreover, teixobactin forms a well-structured and specific complex with lipid II, where the N-terminal part of teixobactin assumes a β conformation that is highly prone to aggregation, which likely contributes to the antibiotic's high bactericidal efficiency. Overall, our study provides several new clues to teixobactin's modes of action.

Graphical abstract: Structural studies suggest aggregation as one of the modes of action for teixobactin

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Publication details

The article was received on 16 Aug 2018, accepted on 19 Sep 2018 and first published on 20 Sep 2018


Article type: Edge Article
DOI: 10.1039/C8SC03655A
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY license
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    Structural studies suggest aggregation as one of the modes of action for teixobactin

    C. Öster, G. P. Walkowiak, D. E. Hughes, A. L. Spoering, A. J. Peoples, A. C. Catherwood, J. A. Tod, A. J. Lloyd, T. Herrmann, K. Lewis, C. G. Dowson and J. R. Lewandowski, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C8SC03655A

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