Binding Modes of Teixobactin to Lipid II: Molecular Dynamics Study

Teixobactin (TXB) is a newly discovered antibiotic targeting the bacterial cell wall precursor Lipid II (L_II). In the present work, four binding modes of TXB on L_II were identified by a contact-map based clustering method. The highly flexible binary complex ensemble was generated by parallel tempering metadynamics simulation in a well-tempered ensemble (PTMetaD-WTE). In agreement with experimental findings, the pyrophosphate group and the attached first sugar subunit of L_II are found to be the minimal motif for stable TXB binding. Three of the four binding modes involve the ring structure of TXB and have relatively higher binding affinities, indicating the importance of the ring motif of TXB in L_II recognition. TXB-L_II complexes with a ratio of 2:1 are also predicted with configurations such that the ring motif of two TXB molecules bound to the pyrophosphate-MurNAc moiety and the glutamic acid residue of one L_II, respectively. Our findings disclose that the ring motif of TXB is critical to L_II binding and novel antibiotics can be designed based on its mimetics.