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Total synthesis of teixobactin.

ABSTRACT: To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product.

SUBMITTER: Jin K

PROVIDER: S-EPMC4976201 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Total synthesis of teixobactin.

Jin Kang K Sam Iek Hou IH Po Kathy Hiu Laam KHL Lin Du'an D Ghazvini Zadeh Ebrahim H EH Chen Sheng S Yuan Yu Y Li Xuechen X

Nature communications 20160803

To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product. ...[more]

PMID: 27484680

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

Project 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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Thiol-ene Enabled Chemical Synthesis of Truncated S-Lipidated Teixobactin Analogs.

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Design, Synthesis, and Study of Lactam and Ring-Expanded Analogues of Teixobactin.

Project description:This paper describes the chemical synthesis, X-ray crystallographic structure, and antibiotic activity assay of lactam analogues of teixobactin and explores ring-expanded analogues of teixobactin with β3-homo amino acids. Lactam analogues of teixobactin containing all four stereoisomers of aza-threonine at position 8 were synthesized on a solid support from commercially available stereoisomeric threonine derivatives. The threonine stereoisomers are converted to the diastereomeric aza-threonines by mesylation, azide displacement, and reduction during the synthesis. d-Aza-Thr8,Arg10-teixobactin exhibits 2-8-fold greater antibiotic activity than the corresponding macrolactone Arg10-teixobactin. Azateixobactin analogues containing other stereoisomers of aza-threonine are inactive. A dramatic 16-128-fold increase in the activity of teixobactin and teixobactin analogues is observed with the inclusion of 0.002% of the mild detergent polysorbate 80 in the MIC assay. The X-ray crystallographic structure of N-Me-d-Gln4,d-aza-Thr8,Arg10-teixobactin reveals an amphipathic hydrogen-bonded antiparallel β-sheet dimer that binds chloride anions. In the binding site, the macrolactam amide NH groups of residues 8, 10, and 11, as well as the extra amide NH group of the lactam ring, hydrogen bond to the chloride anion. The teixobactin pharmacophore tolerates ring expansion of the 13-membered ring to 14-,15-, and 16-membered rings containing β3-homo amino acids with retention of partial or full antibiotic activity.

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X-ray crystallographic structure of a teixobactin analogue reveals key interactions of the teixobactin pharmacophore.

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Alanine scan reveals modifiable residues in teixobactin.

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