Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities

Parmar, Anish and Prior, Stephen H. and Iyer, Abhishek and Vincent, Charlotte S. and Van Lysebetten, Dorien and Breukink, Eefjan and Madder, Annemieke and Taylor, Edward J. and Singh, Ishwar (2017) Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities. Chemical Communications, 53 (12). pp. 1919-2070. ISSN 1359-7345

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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.

Keywords:Antibiotics
Subjects:C Biological Sciences > C720 Biological Chemistry
Divisions:College of Science > School of Life Sciences
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ID Code:25967
Deposited On:01 Feb 2017 15:21

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