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Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics

Author

Listed:
  • Yu Zong

    (Tsinghua University)

  • Fang Fang

    (Tsinghua University)

  • Kirsten J. Meyer

    (Northeastern University, Department of Biology, Boston)

  • Liguo Wang

    (Tsinghua University)

  • Zhihao Ni

    (Tsinghua University)

  • Hongying Gao

    (Tsinghua-Peking Center for Life Sciences, Haidian District)

  • Kim Lewis

    (Northeastern University, Department of Biology, Boston)

  • Jingren Zhang

    (Tsinghua University)

  • Yu Rao

    (Tsinghua University)

Abstract

Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block l-allo-Enduracidine in 30-gram scale in just one hour and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Staphylococcus aureus. We also propose that the antiparallel β-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking.

Suggested Citation

  • Yu Zong & Fang Fang & Kirsten J. Meyer & Liguo Wang & Zhihao Ni & Hongying Gao & Kim Lewis & Jingren Zhang & Yu Rao, 2019. "Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11211-y
    DOI: 10.1038/s41467-019-11211-y
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    Cited by:

    1. Shupeng Yin & Zhi Liu & Jingjing Shen & Yuwei Xia & Weihong Wang & Pengyan Gui & Qian Jia & Konthorn Kachanuban & Weiming Zhu & Peng Fu, 2022. "Chimeric natural products derived from medermycin and the nature-inspired construction of their polycyclic skeletons," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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