Abstract
Teixobactin (TXB) is a newly discovered antibiotic targeting the bacterial cell wall precursor Lipid II (LII). In the present work, four binding modes of TXB on LII 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 LII 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 LII recognition. TXB-LII 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 LII, respectively. Our findings disclose that the ring motif of TXB is critical to LII binding and novel antibiotics can be designed based on its mimetics.
Highlights
Lipid II (LII), one of the most essential intermediate products for the biosynthesis of bacterial cell walls, was recognized as an antibiotic target for decades[1]
One LII molecule is composed of one bactoprenol hydrocarbon chain (C55), which is embedded in the cell membrane, a disaccharide of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), a penta-peptide attached to the MurNAc, and a pyrophosphate group (PP) linking the bactoprenol anchor and MurNAc2,3
With so many polar residues, such as charged residues PP-4, Glu-7, Lys-8, Ala-10 in LII, and the polar ring motif in TXB, a lot of local minima could be foreseen on the free energy surface (FES) of TXB- LII binding
Summary
Lipid II (LII), one of the most essential intermediate products for the biosynthesis of bacterial cell walls, was recognized as an antibiotic target for decades[1]. Preventing the translocation of LII is bona fide strategy to kill bacteria by interfering with a critical step in the cell wall synthetic pathway. Some antibiotics, such as vancomycin, nisin, ramoplanin and mannopeptimycin[2] exert their antimicrobial activity by interacting with LII synthesis. Bacteria develop resistance to vancomycin by mutating the penta-peptide terminus from D-Ala-D-Ala to D-Ala-D-Lac. The binding affinity of vancomycin to the mutated LII is 1000-fold lower mainly due to the introduction of a lone pair repulsion and the loss of central H bonds[10]. The importance of hydrophobicity from the N-terminal tail was discussed in their work: the TXB analogue still remained bactericidal after replacing the residues NmPhe-1 to Ile-5 with a dodecanoyl group
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