| Autor: |
Parmar A; School of Pharmacy, JBL Building, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK. isingh@lincoln.ac.uk., Prior SH; School of Chemistry, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK., Iyer A; School of Pharmacy, JBL Building, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK. isingh@lincoln.ac.uk and Organic and Biomimetic Chemistry Research Group, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium., Vincent CS; School of Life Sciences, Joseph Bank Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK. etaylor@lincoln.ac.uk., Van Lysebetten D; Organic and Biomimetic Chemistry Research Group, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium., Breukink E; Department of Membrane Biochemistry and Biophysics, Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands., Madder A; Organic and Biomimetic Chemistry Research Group, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium., Taylor EJ; School of Life Sciences, Joseph Bank Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK. etaylor@lincoln.ac.uk., Singh I; School of Pharmacy, JBL Building, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK. isingh@lincoln.ac.uk. |
| Abstrakt: |
The discovery of the highly potent antibiotic teixobactin, which kills the bacteria without any detectable resistance, has stimulated interest in its structure-activity relationship. However, a molecular structure-activity relationship has not been established so far for teixobactin. Moreover, the importance of the individual amino acids in terms of their l/d configuration and their contribution to the molecular structure and biological activity are still unknown. For the first time, we have defined the molecular structure of seven teixobactin analogues through the variation of the d/l configuration of its key residues, namely N-Me-d-Phe, d-Gln, d-allo-Ile and d-Thr. Furthermore, we have established the role of the individual d amino acids and correlated this with the molecular structure and biological activity. Through extensive NMR and structural calculations, including molecular dynamics simulations, we have revealed the residues for maintaining a reasonably unstructured teixobactin which is imperative for biological activity. |
