Peptidoglycan biosynthesis

Fosfomycin is an antibiotic produced by several Streptomyces species [95, 96] as well as by the Gram-negative Pseudomonas syringiae and Pseudomonas viridiflava. dl, 98] As an analogue of phosphoenolpyruvate, it irreversibly inhibits UDP-N-acetylglu-cosamine-3-O-enolpymvyltransferase (MurA), the enzyme that catalyzes the first step in peptidoglycan biosynthesis [99]. 

J. M. Frere, B. Joris, Penicillin-Sensitive Enzymes in Peptidoglycan Biosynthesis , Crit. Rev. Microbiol. 1985,1, 299-396. 

Glycopeptides Vancomycin Teicoplanin Reprogramming peptidoglycan biosynthesis... 

Cycloserine (Fig- 4) is produced by several species of Streptomyces. One of the basic glycosyl components of the bacterial cell wall, n-acetyl-muramic acid (the product of Mur A and MurB), is modified by the addition of the first three amino acids sequentially by MurC, MurD and MurE enzymes. A dipeptide, D-alanyl-D-alanine is then added to make the pentapeptide. In bacteria, L-alanine is the native form and it is converted to D-alanine form by alanine racemase (Air). Two D-alanines are joined by D-ala-D-ala ligase (DdlA) to synthesize the dipeptide. Cycloserine resembles the substrate for Air and Ddl and inhibits their respective reactions in stage I of the peptidoglycan biosynthesis (Fig. 2). 

Our studies of the bacterial enzymes utilized in peptidoglycan biosynthesis required an ample supply of both lipid I and lipid II. Isolation of these precursors from bacterial sources presented significant challenges. First, each of these intermediates is present in very low copy numbers. For example, in E. coli, the copy numbers for lipid I and lipid II are estimated to be approximately 700 and 1000-2000 molecules per cell, respectively.9 Second, separation of miniscule amounts of the cell wall precursors from the comparatively large amounts of cellular lipid and membrane components is technically challenging and further compromises the ability to isolate sufficient quantities of the enzyme substrates to enable detailed mechanistic studies.10... 

Bugg TDH (1999) Bacterial peptidoglycan biosynthesis and its inhibition. Comprehensive Natural Products Chemistry, Vol 3. Elsevier, Amsterdam, pp 241-294. 

Bugg TDH and Walsh CT (1992) Intracellular steps of bacterial cell wall peptidoglycan biosynthesis enzymology, antibiotics, and antibiotic resistance. Nat Prod Rep 9, 199-215. 

Ge M, Chen Z, Onishi HR et al (1999) Vancomycin derivatives that inhibit peptidoglycan biosynthesis without binding D-Ala-D-Ala. Science 284 507-511... 

NE Allen, JN Hobbs Jr, TI Nicas. Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic. Antimicrob Agents Chemother 40 2356-2362, 1996. 

Nonetheless, there are several unexploited gene families that may provide additional multigene targets for inhibitors, such as the two-component signal transduction systems [32,51], tRNA synthetases [52], RNA polymerase sigma subunits [53,54], and the aminoacyl ligases of peptidoglycan biosynthesis [55],... 

Humljan, J., Kotnik, M., Boniface, A., et al. (2006) A new approach towards peptidosulfonamides synthesis of potential inhibitors of bacterial peptidoglycan biosynthesis enzymedMurD andMurE. Tetrahedron 62,10980-10899. 

The peptidoglycan layer confers mechanical stability to the cell wall of the bacteria. An important intermediate of the peptidoglycan biosynthesis is the GlcNAc- MurNAc-L-Ala-D-y-Gln-L-Lys-D-Ala-D-Ala peptide (muramyl-pentapeptide), which is in its lipid-carrrier bound form transglycosylated to a linear polysaccharide. The linear polysaccharide is then cross-linked to peptidoglycan by transpeptidation reactions. Perkins observed that vancomycin binds to the Lys-D-Ala-D-Ala peptide motif of bacterial cell wall intermediates. This observation was later investigated on a mole-cular level by NMR and by x-ray crystallographic studies. ... 

Wong KK, Pompliano DL. Peptidoglycan biosynthesis. Unexploited antibacterial targets within a familiar pathway. Adv. Exp. Med. Biol. 1998 456 197-217. 

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