ABSTRACT
Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo-enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0.25 to 1.0⯵M. Structure-activity relationship is also established for further development of more promising teixobactin analogues.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Depsipeptides/chemistry , Pyrrolidines/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cyclization , Depsipeptides/chemical synthesis , Depsipeptides/pharmacology , Gram-Positive Bacteria/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
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.
