Investigation of the N-Terminus Amino Function of Arg10-Teixobactin

Teixobactin is a recently described antimicrobial peptide that shows high activity against gram-positive bacteria as well as mycobacterium tuberculosis. Due to both its structure as a head-to-side chain cyclodepsipeptide and its activity, it has attracted the attention of several research groups. In this regard, a large number of analogs with substitutions in both the cycle and the tail has been described. Here, we report the contribution of the N-terminus residue, N-Me-d-Phe, to the activity of Arg10-teixobactin. On the basis of our findings, we conclude that the N-terminus accepts minimum changes but not the presence of long alkyl chains. The presence of a positive charge is a requirement for the activity of the peptide. Furthermore, acylation of the N-terminus leads to total loss of activity.

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

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

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

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

[5]  Yahya E. Jad,et al.  Re-evaluation of the N-terminal substitution and the D-residues of teixobactin , 2016 .

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

[7]  F. Albericio,et al.  An improved and efficient strategy for the total synthesis of a colistin-like peptide , 2016 .

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

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

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

[11]  J. Adán,et al.  Tackling lipophilicity of peptide drugs: replacement of the backbone N-methyl group of cilengitide by N-oligoethylene glycol (N-OEG) chains. , 2014, Bioconjugate chemistry.

[12]  M. Vaara,et al.  Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells , 2012, Peptides.

[13]  A. Schmidtchen,et al.  Effects of peptide hydrophobicity on its incorporation in phospholipid membranes--an NMR and ellipsometry study. , 2011, Biochimica et biophysica acta.

[14]  M. Takano,et al.  Novel Polymyxin Derivatives Carrying Only Three Positive Charges Are Effective Antibacterial Agents , 2008, Antimicrobial Agents and Chemotherapy.

[15]  N. Sakura,et al.  Semi-synthesis of Polymyxin B (2-10) and Colistin (2-10) Analogs Employing the Trichloroethoxycarbonyl (Troc) Group for Side Chain Protection of α,γ-Diaminobutyric Acid Residues , 2007 .

[16]  E. Giralt,et al.  Solid-phase synthesis and characterization of N-methyl-rich peptides. , 2008, The journal of peptide research : official journal of the American Peptide Society.

[17]  Rubin Gulaboski,et al.  Lipophilicity of Peptide Anions: An Experimental Data Set for Lipophilicity Calculations , 2003 .

[18]  M. Fridkin,et al.  N-terminal modifications of Polymyxin B nonapeptide and their effect on antibacterial activity , 2001, Peptides.

[19]  F. Albericio,et al.  Substituted guanidines: introducing diversity in combinatorial chemistry. , 2000, Organic letters.

[20]  N. Araki,et al.  Improvement of Transdermal Delivery of Tetragastrin by Lipophilic Modification with Fatty Acids , 1995, The Journal of pharmacy and pharmacology.