Staphylococcus aureus Penicillin-Binding Protein2 Can Use Depsi-LipidII Derived from Vancomycin-Resistant Strains for Cell Wall Synthesis

Vancomycin-resistant Staphylococcus aureus (S. aureus) (VRSA) uses depsipeptide-containing modified cell-wall precursors for the biosynthesis of peptidoglycan. Transglycosylase is responsible for the polymerization of the peptidoglycan, and the penicillin-binding protein2 (PBP2) plays a major role in the polymerization among several transglycosylases of wild-type S. aureus. However, it is unclear whether VRSA processes the depsipeptide-containing peptidoglycan precursor by using PBP2. Here, we describe the total synthesis of depsi-lipidI, a cell-wall precursor of VRSA. By using this chemistry, we prepared a depsi-lipidII analogue as substrate for a cell-free transglycosylation system. The reconstituted system revealed that the PBP2 of S. aureus is able to process a depsi-lipidII intermediate as efficiently as its normal substrate. Moreover, the system was successfully used to demonstrate the difference in the mode of action of the two antibiotics moenomycin and vancomycin. Break the resistance: The first total synthesis of depsi-lipidI (see scheme), a cell-wall precursor of vancomycin-resistant Staphylococcus aureus (S. aureus) (VRSA), was accomplished. Kinetic analysis of the transglycosylation of S. aureus by using a depsi-lipid-substrate and the mode of action analysis of cell-wall-targeting antibiotics are also described.