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

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  a...

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Autores principales: Zong, Yu, Fang, Fang, Meyer, Kirsten J., Wang, Liguo, Ni, Zhihao, Gao, Hongying, Lewis, Kim, Zhang, Jingren, Rao, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646333/
https://www.ncbi.nlm.nih.gov/pubmed/31332172
http://dx.doi.org/10.1038/s41467-019-11211-y
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author Zong, Yu
Fang, Fang
Meyer, Kirsten J.
Wang, Liguo
Ni, Zhihao
Gao, Hongying
Lewis, Kim
Zhang, Jingren
Rao, Yu
author_facet Zong, Yu
Fang, Fang
Meyer, Kirsten J.
Wang, Liguo
Ni, Zhihao
Gao, Hongying
Lewis, Kim
Zhang, Jingren
Rao, Yu
author_sort Zong, Yu
collection PubMed
description 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.
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spelling pubmed-66463332019-07-24 Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics Zong, Yu Fang, Fang Meyer, Kirsten J. Wang, Liguo Ni, Zhihao Gao, Hongying Lewis, Kim Zhang, Jingren Rao, Yu Nat Commun Article 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. Nature Publishing Group UK 2019-07-22 /pmc/articles/PMC6646333/ /pubmed/31332172 http://dx.doi.org/10.1038/s41467-019-11211-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zong, Yu
Fang, Fang
Meyer, Kirsten J.
Wang, Liguo
Ni, Zhihao
Gao, Hongying
Lewis, Kim
Zhang, Jingren
Rao, Yu
Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
title Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
title_full Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
title_fullStr Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
title_full_unstemmed Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
title_short Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
title_sort gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646333/
https://www.ncbi.nlm.nih.gov/pubmed/31332172
http://dx.doi.org/10.1038/s41467-019-11211-y
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