Synthesis and structure-activity relationship of teixobactin analogues via convergent Ser ligation

Abstract

Convergent Ser/Thr ligation has been used to prepare a series of teixobactin analogues (28 in total) to establish a structure-activity relationship of teixobactin. anti-bacterial evaluations of these synthetic analogues have revealed the critical amino acid residues and the sites tolerable of modifications. These studies will shed lights on the further development of teixobactin analogues with improved antibacterial activities.

Probing key elements of teixobactin–lipid II interactions in membranes

“…15 and 17 and 27) but not Ile11 15,27. In contrast, some hydrophobic substitutions of Ile11 retain partial activity 15,16,27. Both results indicate that Ile11 is more likely the membrane anchor of the cyclodepsipeptide ring than Ala9 in vivo , matching the membrane binding mode described in System 6.…”

“…This means hydrophobic interactions are expected to play significant roles in Txb's activity. Granted, most known Txb analogs with substituted mid-chain hydrophobic residues lose their antimicrobial activities,11,15,16,22 indicating that hydrophobic interactions are indeed essential for Txb–lipid II binding.…”

Syntheses of potent teixobactin analogues against methicillin-resistant Staphylococcus aureus (MRSA) through the replacement of l-allo-enduracididine with its isosteres

“…The syntheses and biological activity against Staphylococcus aureus of Lys10-teixobactin (1) 8 12 , Orn10-teixobactin (3) 5 , Arg10-teixobactin (4) 6 7 and NorArg10-teixobactin 13 have already been reported. There has been very limited evaluation of teixobactin analogues against MRSA.…”

“…There has been very limited evaluation of teixobactin analogues against MRSA. Among the synthesised analogues, Orn10-teixobactin (3) (MIC 2 µg/mL) 5 and NorArg10-teixobactin 13 (MIC 16 µg/mL) 13 are the only ones tested against MRSA. However, a different strain of MRSA was used.…”

“…which reports the synthesis and antibacterial activity of NorArg10-teixobactin. 13 To further develop potent teixobactin analogues against resistant bacteria such as MRSA, we are particularly interested in understanding the role of the polar amino acid residues at position 10 namely L-allo-enduracididine, arginine and lysine. It has been suggested that L-allo-enduracididine is important for the biological activity of teixobactin.…”