Issue 47, 2018

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
16 Aug 2018
Accepted
19 Sep 2018
First published
20 Sep 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 8850-8859

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, 9, 8850 DOI: 10.1039/C8SC03655A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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