Peptidoglycan polymerization

H Suzuki, Y van Heijenoort, T Tamura, J Mizoguchi, Y Hirota, J van Heijenoort. In vitro peptidoglycan polymerization catalyzed by penicillin binding protein lb of Escherichia coli K-12. FEMS Microbiol Lett 110 245-249, 1980. 

Mode of action Vancomycin inhibits synthesis of bacterial cell wall phospholipids as well as peptidoglycan polymerization at a site earlier than that inhibited by the p-lactam antibiotics. 

M, Aszodi J, Ayala JA, Ghuysen JM, Nguyen- Disteche M. The catalytic, glycosyl transferase and acyl transferase modules of the cell wall peptidoglycan-polymerizing penicillin-binding protein lb of Escherichia coli. Mol. Microbiol. 1999 34 350-364. 

In a final example specifically devoted to the use of mercury reagents following Wittig olefinations, Qiao, et al.,6 utilized mercuric trifluoroacetate to effect ring closure. This example, shown in Scheme 7.1.6, was utilized in the synthesis of the C-phosphonate disaccharide, shown in Figure 7.1.1, as a potential inhibitor of peptidoglycan polymerization by transglycosylase. 

The glycopeptides include vancomycin and teico-planin. They are bactericidal antibiotics. Their mechanism of action is based on inhibition of bacterial cell-wall synthesis by blocking the polymerization of glycopeptides. They do not act from within the peptidoglycan layer, as the beta-lactam antibiotics do, but intracellularly. The indications are mainly restricted to the management of severe or resistant staphylococcal infections, especially those caused by coagulase negative staphylococcal species such as S. epidermidis. 

The glycopeptides are inhibitors of cell wall synthesis. They bind to the terminal carboxyl group on the d-alanyl-D-alanine terminus of the A-acetylglucosamine-A-acetylmuramic acid peptide and prevent polymerization of the linear peptidoglycan by peptidoglycan synthase. They are bactericidal in vitro. 

Principles to stabilize lipid bilayers by polymerization have been outlined schematically in Fig. 4a-d. Mother Nature — unfamiliar with the radically initiated polymerization of unsaturated compounds — uses other methods to-stabilize biomembranes. Polypeptides and polysaccharide derivatives act as a type of net which supports the biomembrane. Typical examples are spectrin, located at the inner surface of the erythrocyte membrane, clathrin, which is the major constituent of the coat structure in coated vesicles, and murein (peptidoglycan) a macromolecule coating the bacterial membrane as a component of the cell wall. Is it possible to mimic Nature and stabilize synthetic lipid bilayers by coating the liposome with a polymeric network without any covalent linkage between the vesicle and the polymer One can imagine different ways for the coating of liposomes with a polymer. This is illustrated below in Fig. 53. 

When UDP-GlcNAc was incubated with membranes from Bacillussubtilis, synthesis of polyprenyl diphosphate-linked tetra- and hexa-saccharides composed of 2-acetamido-2-deoxy-D-glucosyl residues was observed,399 and the process may be similar to the polymerization of peptidoglycan precursors discussed in the next Section. 

Biosynthesis of bacterial cell wall is remarkable in two respects (1) It entails the synthesis of a regularly cross-linked polymer and (2) Part of the synthesis takes place inside the cell and part outside the cell. The synthesis of cell wall is divided into three stages, which occur at different locations (1) synthesis of UDP-/V-acetylmuramyl-penta-peptide, (2) polymerization of IV-acetylglucosamine and N-acetylmuramyl-pentapeptide to form linear peptidoglycan strands, and (3) cross-linking of the peptidoglycan strands. 

Figure 2 Mode of action of the prototypical lantibiotic nisin. (a) The peptidoglycan precursor lipid II is composed of an N-acetylglucosamine-p-1,4-N-acetylmuramic acid disaccharide (GIcNAc-MurNAc) that is attached to a membrane anchor of 11 isoprene units via a pyrophosphate moiety. A pentapeptide is linked to the muramic acid. Transglycosylase and transpeptidase enzymes polymerize multiple lipid II molecules and crosslink their pentapeptide groups, respectively, to generate the peptidoglycan. (b) The NMR solution structure of the 1 1 complex of nisin and a lipid II derivative in DMSO (6). (c) The amino-terminus of nisin binds the pyrophosphate of lipid II, whereas the carboxy-terminus inserts into the bacterial membrane. Four lipid II and eight nisin molecules compose a stable pore, although the arrangement of the molecules within each pore is unknown (5).

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