| Autor: |
Öster C; Department of Chemistry , University of Warwick , Coventry , CV4 7AL , UK . Email: j.r.lewandowski@warwick.ac.uk., Walkowiak GP; Department of Chemistry , University of Warwick , Coventry , CV4 7AL , UK . Email: j.r.lewandowski@warwick.ac.uk.; School of Life Sciences , University of Warwick , Coventry , CV4 7AL , UK., Hughes DE; NovoBiotic Pharmaceuticals , Cambridge , MA 02138 , USA., Spoering AL; NovoBiotic Pharmaceuticals , Cambridge , MA 02138 , USA., Peoples AJ; NovoBiotic Pharmaceuticals , Cambridge , MA 02138 , USA., Catherwood AC; School of Life Sciences , University of Warwick , Coventry , CV4 7AL , UK., Tod JA; School of Life Sciences , University of Warwick , Coventry , CV4 7AL , UK., Lloyd AJ; School of Life Sciences , University of Warwick , Coventry , CV4 7AL , UK., Herrmann T; Univ. Grenoble Alpes , CNRS , CEA , IBS , F-38000 Grenoble , France., Lewis K; Antimicrobial Discovery Center , Northeastern University , Department of Biology , Boston , MA 02115 , USA., Dowson CG; School of Life Sciences , University of Warwick , Coventry , CV4 7AL , UK., Lewandowski JR; Department of Chemistry , University of Warwick , Coventry , CV4 7AL , UK . Email: j.r.lewandowski@warwick.ac.uk. |
| Abstrakt: |
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. |
