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

Abstract

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.

Rational Design and Synthesis of Modified Teixobactin Analogues: In Vitro Antibacterial Activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa

“…In lesst han three years since its discovery, more than ah undred analogues have been synthesised by various research groups in the hope of elucidating itsstructure-activity relationships (SARs). [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] The biological activities of these analogues and the different synthetic strategies reported have been comprehensively reviewed. [38,39] X-ray crystallographic, molecular dynamic and NMR structural studies have also been conducted to construct possible binding models of the native peptide and its analogues.…”

The impact of backbone N‐methylation on the structure‐activity relationship of Leu10‐teixobactin

“…For example, adding an additional methyl group to the already N-methylated N-terminus reduced potency by eight-fold in the Arg 10 -teixobactin analogue. 29 Given that N-methylation of one or more of the macrocyclic amides would likely introduce conformational or steric constraints and directly interfere with pyrophosphate binding, we focussed our current investigation to the effect of N-methylating 30 residues 2-7 of Leu 10 -teixobactin ( Figure 3). The antimicrobial activity of the N-methyl analogues against four S.…”

N‐methylation in amino acids and peptides: Scope and limitations

“…Several examples have been reported discussing the difficulties encountered with the acetylation the N ‐Me peptide terminals. For instance, Abdel Monaim et al described the cleavage of the Dec‐ N ‐Me‐D‐Phe 1 ‐terminal during the synthesis of Dec‐ N ‐Me‐D‐Phe 1 ‐Arg 10 ‐teixobactin, and only the mass of NH 2 ‐Ile 2 ‐Arg 10 ‐teixobactin was detected (Figure ).…”