Total synthesis of teixobactin and its stereoisomers

Teixobactin is a depsipeptide natural product with potent antibiotic activity against a range of Gram-positive multi-drug resistant bacteria. Its composition features a unique L-allo-enduracididine (allo-End10), three Iles2/6/11 residues, and one D-allo-Ile5 residue. Intrigued by the potential biological impact of the stereochemistry of these residues, we synthesized teixobactin and three of its stereoisomers carrying L-End10, D-End10 or D-allo-End10. In addition, stereoisomers with D-allo-Ile shuffled to positions 2, 6 or 11 were prepared. Our synthetic strategy uses the combined methods of solution and solid phase peptide synthesis. The solution phase synthesis overcomes the racemization issue for ester coupling between Ile11 and Thr8. The solid phase synthesis improves efficiency and convergence. This method also allows the efficient preparation of fluorescent-labeled analogs of teixobactin.

[1]  Yahya E. Jad,et al.  Teixobactin as a scaffold for unlimited new antimicrobial peptides: SAR study. , 2017, Bioorganic & medicinal chemistry.

[2]  J. Nowick,et al.  Alanine scan reveals modifiable residues in teixobactin. , 2017, Chemical communications.

[3]  E. Breukink,et al.  Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding† †Electronic supplementary information (ESI) available: Peptide synthesis, HPLC, LC-MS analysis, NMR spectra, microbiological data (MIC, MBC, time kill kinetics), lipid II an , 2017, Chemical science.

[4]  F. Albericio,et al.  Investigation of the N-Terminus Amino Function of Arg10-Teixobactin , 2017, Molecules.

[5]  F. Albericio,et al.  Converting Teixobactin into a Cationic Antimicrobial Peptide (AMP). , 2017, Journal of medicinal chemistry.

[6]  A. Madder,et al.  Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus (MRSA) through the replacement of l-allo-enduracididine with its isosteres. , 2017, Chemical communications.

[7]  J. Ziller,et al.  X-ray crystallographic structure of a teixobactin analogue reveals key interactions of the teixobactin pharmacophore. , 2017, Chemical communications.

[8]  E. Breukink,et al.  Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities. , 2017, Chemical communications.

[9]  Z. Pan,et al.  Synthesis and structure–activity relationship studies of teixobactin analogues , 2017 .

[10]  Yahya E. Jad,et al.  Lysine Scanning of Arg10–Teixobactin: Deciphering the Role of Hydrophobic and Hydrophilic Residues , 2016, ACS omega.

[11]  Ebrahim H Ghazvini Zadeh,et al.  Total synthesis of teixobactin , 2016, Nature Communications.

[12]  Kevin H. Chen,et al.  Elucidation of the Teixobactin Pharmacophore. , 2016, ACS chemical biology.

[13]  Roger G. Linington,et al.  Total Synthesis of Teixobactin. , 2016, Organic letters.

[14]  A. Madder,et al.  Efficient total syntheses and biological activities of two teixobactin analogues. , 2016, Chemical communications.

[15]  G. He,et al.  Total Synthesis of Mannopeptimycins α and β. , 2016, Journal of the American Chemical Society.

[16]  Yahya E. Jad,et al.  Synthesis and Biological Evaluation of a Teixobactin Analogue. , 2015, Organic letters.

[17]  K. Lewis,et al.  A new antibiotic kills pathogens without detectable resistance , 2015, Nature.

[18]  Johann H. Sattler,et al.  Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones. , 2014, Organic & biomolecular chemistry.

[19]  S. Walker,et al.  Haloduracin α Binds the Peptidoglycan Precursor Lipid II with 2:1 Stoichiometry , 2011, Journal of the American Chemical Society.

[20]  E. Breukink,et al.  Lipid II as a target for antibiotics , 2006, Nature Reviews Drug Discovery.

[21]  R. Kaptein,et al.  The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics , 2004, Nature Structural &Molecular Biology.

[22]  P. Bradford,et al.  Mechanism of Action of the Mannopeptimycins, a Novel Class of Glycopeptide Antibiotics Active against Vancomycin-Resistant Gram-Positive Bacteria , 2004, Antimicrobial Agents and Chemotherapy.

[23]  S. Walker,et al.  Ramoplanin inhibits bacterial transglycosylases by binding as a dimer to lipid II. , 2003, Journal of the American Chemical Society.

[24]  R. Williamson,et al.  Mannopeptimycins, novel antibacterial glycopeptides from Streptomyces hygroscopicus, LL-AC98. , 2002, Journal of the American Chemical Society.

[25]  Murray Goodman,et al.  Triurethane-Protected Guanidines and Triflyldiurethane-Protected Guanidines: New Reagents for Guanidinylation Reactions , 1998 .

[26]  Konrad Feichtinger,et al.  Diprotected Triflylguanidines: A New Class of Guanidinylation Reagents , 1998 .

[27]  A. Göpferich,et al.  Labelling peptides with fluorescent probes for incorporation into degradable polymers. , 1998, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[28]  M. Asai,et al.  Enduracidin, a New Antibiotic. VIII. Structures of Enduracidins A and B , 1973 .