title: Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities.
abstract: 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.
authors.affiliation: School of Pharmacy, JBL Building, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK. isingh@lincoln.ac.uk.
authors.forename: Anish
authors.initials: A
authors.lastname: Parmar
authors.affiliation: School of Chemistry, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Prior
authors.affiliation: 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.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Iyer
authors.affiliation: School of Life Sciences, Joseph Bank Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK. etaylor@lincoln.ac.uk.
authors.forename: Charlotte S
authors.initials: CS
authors.lastname: Vincent
authors.affiliation: Organic and Biomimetic Chemistry Research Group, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Van Lysebetten
authors.affiliation: Department of Membrane Biochemistry and Biophysics, Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.affiliation: Organic and Biomimetic Chemistry Research Group, Department of Organic Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Madder
authors.affiliation: School of Life Sciences, Joseph Bank Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK. etaylor@lincoln.ac.uk.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Taylor
authors.affiliation: School of Pharmacy, JBL Building, University of Lincoln, Beevor St., Lincoln LN6 7DL, UK. isingh@lincoln.ac.uk.
authors.forename: Ishwar
authors.identifier: http://orcid.org/0000-0001-7822-1063
authors.initials: I
authors.lastname: Singh
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D047630:Depsipeptides; C000594838:teixobactin