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Binding Modes of Teixobactin to Lipid II: Molecular Dynamics Study.

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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5722933 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Binding Modes of Teixobactin to Lipid II: Molecular Dynamics Study.

Liu Yang Y Liu Yaxin Y Chan-Park Mary B MB Mu Yuguang Y

Scientific reports 20171208 1

Teixobactin (TXB) is a newly discovered antibiotic targeting the bacterial cell wall precursor Lipid II (L<sub>II</sub>). In the present work, four binding modes of TXB on L<sub>II</sub> 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<s ...[more]

PMID: 29222455

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Project description:Teixobactin is a highly promising antibacterial depsipeptide consisting of four d-amino acids and a rare l-allo-enduracididine amino acid. l-allo-Enduracididine is reported to be important for the highly potent antibacterial activity of teixobactin. However, it is also a key limiting factor in the development of potent teixobactin analogues due to several synthetic challenges such as it is not commercially available, requires a multistep synthesis, long and repetitive couplings (16-30 hours). Due to all these challenges, the total synthesis of teixobactin is laborious and low yielding (3.3%). In this work, we have identified a unique design and developed a rapid synthesis (10 min ?wave assisted coupling per amino acid, 30 min cyclisation) of several highly potent analogues of teixobactin with yields of 10-24% by replacing the l-allo-enduracididine with commercially available non-polar residues such as leucine and isoleucine. Most importantly, the Leu10-teixobactin and Ile10-teixobactin analogues have shown highly potent antibacterial activity against a broader panel of MRSA and Enterococcus faecalis (VRE). Furthermore, these synthetic analogues displayed identical antibacterial activity to natural teixobactin (MIC 0.25 ?g mL-1) against MRSA ATCC 33591 despite their simpler design and ease of synthesis. We have confirmed lipid II binding and measured the binding affinities of individual amino acid residues of Ala10-teixobactin towards geranyl pyrophosphate by NMR to understand the nature and strength of binding interactions. Contrary to current understanding, we have shown that a cationic amino acid at position 10 is not essential for target (lipid II) binding and potent antibacterial activity of teixobactin. We thus provide strong evidence contrary to the many assumptions made about the mechanism of action of this exciting new antibiotic. Introduction of a non-cationic residue at position 10 allows for tremendous diversification in the design and synthesis of highly potent teixobactin analogues and lays the foundations for the development of teixobactin analogues as new drug-like molecules to target MRSA and Mycobacterium tuberculosis.

Project description:Teixobactin (Txb) is a recently discovered antibiotic against Gram-positive bacteria that induces no detectable resistance. The bactericidal mechanism is believed to be the inhibition of cell wall biosynthesis by Txb binding to lipid II and lipid III. Txb binding specificity likely arises from targeting of the shared lipid component, the pyrophosphate moiety. Despite synthesis and functional assessment of numerous chemical analogs of Txb, and consequent identification of the Txb pharmacophore, the detailed structural information of Txb-substrate binding is still lacking. Here, we use molecular modeling and microsecond-scale molecular dynamics simulations to capture the formation of Txb-lipid II complexes at a membrane surface. Two dominant binding conformations were observed, both showing characteristic lipid II phosphate binding by the Txb backbone amides near the C-terminal cyclodepsipeptide (d-Thr8-Ile11) ring. Additionally, binding by Txb also involved the side chain hydroxyl group of Ser7, as well as a secondary phosphate binding provided by the side chain of l-allo-enduracididine. Interestingly, those conformations differ by swapping two groups of hydrogen bond donors that coordinate the two phosphate moieties of lipid II, resulting in opposite orientations of lipid II binding. In addition, residues d-allo-Ile5 and Ile6 serve as the membrane anchors in both Txb conformations, regardless of the detailed phosphate binding interactions near the cyclodepsipeptide ring. The role of hydrophobic residues in Txb activity is primarily for its membrane insertion, and subsidiarily to provide non-polar interactions with the lipid II tail. Based on the Txb-lipid II interactions captured in their complexes, as well as their partitioning depths into the membrane, we propose that the bactericidal mechanism of Txb is to arrest cell wall synthesis by selectively inhibiting the transglycosylation of peptidoglycan, while possibly leaving the transpeptidation step unaffected. The observed "pyrophosphate caging" mechanism of lipid II inhibition appears to be similar to some lantibiotics, but different from that of vancomycin or bacitracin.

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Binding Modes of Teixobactin to Lipid II: Molecular Dynamics Study.

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Binding Modes of Teixobactin to Lipid II: Molecular Dynamics Study.

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