Synthesis and biological evaluation of novel teixobactin analogues

Abstract

The cyclic depsipeptide, teixobactin, possesses promising activity against a range of antimicrobial-resistant (AMR) pathogenic bacteria, including Staphylococcus aureus and Mycobacterium tuberculosis. Teixobactin contains a number of non-canonical residues, including the synthetically challenging amino acid, l-allo-enduracididine, complicating clinical application of this peptide. Herein, we report the synthesis of six analogues of teixobactin, in which the non-canonical l-allo-enduracididine amino acid is replaced by isosteric, commercially available Fmoc-amino acid building blocks. Biological evaluation of the analogues has revealed promising activity, particularly for guanidine isosteres, against AMR strains of S. aureus and Enterococcus faecalis, highlighting the potential for this class of cyclic depsipeptides in the treatment of Gram-positive infections.

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

“…Teixobactin ( 1 ), comprised of a 13‐membered depsipeptide core and a tethered linear heptapeptide, offers multiple sites for synthetic modifications to improve its potency and efficacy. In less than three years since its discovery, more than a hundred analogues have been synthesised by various research groups in the hope of elucidating its structure–activity relationships (SARs) . The biological activities of these analogues and the different synthetic strategies reported have been comprehensively reviewed .…”

“…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.…”

Lipopeptidomimetics derived from teixobactin have potent antibacterial activity against Staphylococcus aureus

“…Lys 10farnesylbactin 2 was designed as a result of a previous report suggesting that lysine is a better mimic of the enduracididine residue than arginine. 15 This proved to be the case and provided compound 2 as a more potent analogue (8 mg mL À1 ). Surprisingly compound 2 was also active against the Gram negative E. coli bacterial strain.…”

“…Several groups have reported the synthesis and antimicrobial activity of analogues in which the non-proteinogenic L-allo-enduracididine residue is substituted with isosteric amino acids. [12][13][14][15] A Fmoc-solid phase peptide synthesis (SPPS) strategy was employed, with orthogonal protection to give the branched side chain, before cyclisation to form the 13-membered depsipeptide ring in solution. The teixobactin analogue with single End10 to Arg amino acid substitution was found to have substantial antimicrobial activity, with a minimum inhibitory concentration (MIC) value of 2 mg mL À1 , yet still 8 times weaker than Teixobactin.…”

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

“…6 Several groups have reported the chemical synthesis of both native teixobactin 7,8 and various analogues 9,10 by 9fluorenylmethyloxycarbonyl (Fmoc) solid-phase peptide synthesis (SPPS). To date, three generic synthetic strategies have been established: (a) a stepwise synthesis and solution phase cyclisation 6,8,[11][12][13][14] ; (b) a stepwise synthesis and "on-resin" cyclisation 15,16 ; and (c) a convergent strategy. 7,17 Effective structureactivity relationship (SAR) studies of teixobactin necessitates a synthetic route that is both rapid and efficient.…”