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Structural studies suggest aggregation as one of the modes of action for teixobactin
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Öster, Carl, Walkowiak, Grzegorz P., Hughes, Dallas E., Spoering, Amy L., Peoples, Aaron J., Catherwood, Anita C., Tod, Julie A., Lloyd, Adrian J., Herrmann, Torsten, Lewis, Kim, Dowson, Christopher G. and Lewandowski, Józef R. (2018) Structural studies suggest aggregation as one of the modes of action for teixobactin. Chemical Science, 9 (47). pp. 8850-8859. doi:10.1039/c8sc03655a
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Official URL: https://doi.org/10.1039/c8sc03655a
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 b 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.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Science > Chemistry | ||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Antibiotics, Biosynthesis, Lipids, Nuclear magnetic resonance, Drug resistance in microorganisms | ||||||||||||||||||||||||||||||
| Journal or Publication Title: | Chemical Science | ||||||||||||||||||||||||||||||
| Publisher: | Royal Society of Chemistry | ||||||||||||||||||||||||||||||
| ISSN: | 2041-6520 | ||||||||||||||||||||||||||||||
| Official Date: | 21 December 2018 | ||||||||||||||||||||||||||||||
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| Volume: | 9 | ||||||||||||||||||||||||||||||
| Number: | 47 | ||||||||||||||||||||||||||||||
| Page Range: | pp. 8850-8859 | ||||||||||||||||||||||||||||||
| DOI: | 10.1039/c8sc03655a | ||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access | ||||||||||||||||||||||||||||||
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