The Necessity of d-Thr in the New Antibiotic Teixobactin: A Molecular Dynamics Study

Ever since the discovery of the new antibiotic teixobactin, studies of its structure-activity relationships have never ceased. Here we focus on the chirality of the threonine (Thr) residue, which belongs to the ring motif of teixobactin and plays an important role in the binding with its target, lipid II molecule. We study the structural propensity of the open and closed ring motifs with different chiral Thr residues as well as the teixobactin-lipid II complex with the help of molecular dynamics simulations. Our results suggest that different chiralities lead to different NH orientations of Thr with respect to the ring plane. Only in the closed ring motif with d-Thr is a favored binding cavity achievable with all four NH groups facing the same side of the ring plane. This study develops a deeper understanding of the binding mechanism of teixobactin and lipid II and is expected to be beneficial to new teixobactin-based drug design.