Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA)

Abstract

Teixobactin is a highly potent cyclic depsipeptide which kills a broad range of multi-drug resistant, Gram-positive bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA) without detectable resistance. In this work, we describe the design and rapid synthesis of novel teixobactin analogues containing two cysteine moieties, and the corresponding disulfide-bridged cyclic analogues. These analogues differ from previously reported analogues, such as an Arg10-teixobactin, in terms of their macrocyclic ring size, and feature a disulfide bridge instead of an ester linkage. The new teixobactin analogues were screened against Methicillin-resistant Staphylococcus aureus and Methicillin-sensitive Staphylococcus aureus. Interestingly, one teixobactin analogue containing all l-amino acid building blocks showed antibacterial activity against MRSA for the first time. Our data indicates that macrocyclisation of teixobactin analogues with disulfide bridging is important for improved antibacterial activity. In our work, we have demonstrated the unprecedented use of a disulfide bridge in constructing the macrocyclic ring of teixobactin analogues.

Synthesis and structure−activity relationships of teixobactin

“…8C). 42 This enables cyclization to proceed under ambient conditions and without the use of orthogonal protecting groups.…”

“…As expected, antimicrobial activity is abolished for linear analogues 31 and when the stereochemistry is inverted. 29b,31,51 Replacement of the lactone with a disulfide bond also results in redundant analogues 42 but moderate activity is retained when a lactam is introduced via D-diaminopropionic acid (Dap). 54 When the more isosterically similar (2R,3S)-MeDap is incorporated, antimicrobial activity is improved, 30,36 which could be owing to the enhanced stability of the amide bond compared with the ester bond.…”

“…49 This knowledge helped inform the design of potent Leu/Ile 10 analogues with arginine substitutions at positions 3, 4, and 9, to mimic the net charge of the native peptide. 42 The lysine scan has also been conducted; substitution of all hydrophobic residues abolished activity but was tolerated for polar noncharged residues. 53 A similar study was performed whereby the net charge of teixobactin analogues was increased via incorporation of lysine and 2,3-diaminopropionic acid residues.…”

Teixobactin: a novel anti-infective agent

“…The group established that the D-amino acids are critical for the antimicrobial activity of these analogs, setting stage for the development of additional analogs with antimicrobial activity [18]. Recent data indicates that macrocyclisation of teixobactin analogs with disulfide bridging is also important for antibacterial activity [19].…”

Synthesis of Disulfide‐Bridged N‐Phenyl‐N′‐(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities

“…These peptides have been shown to possess protective effects against antibacterial infections in the living hosts . Disulfide bond containing analogs of vancomycin ( Figure ) and teixobactin, well‐known antibacterial compounds, have been reported with improved antibacterial activities. Consequently, combining the pharmacophores in the same molecule by using a disulfide bond is a rational approach to obtain novel antimicrobial agents.…”