The first total synthesis of lipid II: the final monomeric intermediate in bacterial cell wall biosynthesis.
Bacterial peptidoglycan is composed of a network of beta-[1,4]-linked glyan strands that are cross-linked through pendant peptide chains. The final product, the murein sacculus, is a single, covalently closed macromolecule that precisely defines the size and shape of the bacterial cell. The recent increase in bacterial resistance to cell wall active agents has led to a resurgence of activity directed toward improving our understanding of the resistance mechanisms at the molecular level. The biosynthetic enzymes and their natural substrates can be invaluable tools in this endeavor. While modern experimental techniques have led to isolation and purification of the biosynthetic enzymes utilized in peptidoglycan biosynthesis, securing useful quantities of their requisite substrates from natural substrates has remained problematic. In an effort to address this issue, we report the first total synthesis of lipid II (4), the final monomeric intermediate utilized by Gram positive bacteria for peptidoglycan biosynthesis.
VanNieuwenhze
Michael S
MS
Discovery Chemistry Research and the Department of Pharmaceutical and Analytical Chemistry, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. msv@lilly.com
Mauldin
Scott C
SC
Zia-Ebrahimi
Mohammad
M
Winger
Brian E
BE
Hornback
William J
WJ
Saha
Shankar L
SL
Aikins
James A
JA
Blaszczak
Larry C
LC
D002240:Carbohydrate Sequence; D002473:Cell Wall / Q000378:metabolism; D008969:Molecular Sequence Data; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D014539:Uridine Diphosphate Sugars / Q000138:chemical synthesis*
D014538:Uridine Diphosphate N-Acetylmuramic Acid; D014539:Uridine Diphosphate Sugars; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; C020949:uridine diphosphate N-acetyl-D-mannosaminuronic acid