Biosynthesis of Peptidoglycans

An understanding of the biochemistry of peptidoglycan (PG murein) that comprises bacterial cell walls is very important medically since blockage of its synthesis was the first, and continues to be a primary, point of attack in the control of bacterial infection. In addition to inhibition of cell wall synthesis, antimicrobial drug s main mechanisms are interference with nucleic acid synthesis, inhibition of folate metabolism, and binding to ribosomes to disrupt protein synthesis (Table 16-2). 

PG biosynthesis involves about 30 enzymes and occurs in three stages  

Inhibition of cell-wall synthesis 3-Lactams Vancomycin 

Ribosomal binding Tetracyclines Macrolides Chloramphenicol Clindamycin Aminoglycosides 

Interference with nucleic acid synthesis Quinolones Rifampin Metronidazole 

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Fig. 8.1 Biosynthesis of peptidoglycan. The large circles represent A -acetylglucosamine orN-acetylmuramic acid to the latter is linked initially a pentapeptide chain comprising L-alanine, D-glutamic acid and meso-diaminopiraelic acid (small circles) terminating in two D-alanine residues (small, darker circles). The lipid molecule is undecaprenyl phosphate. In the initial (cytoplasm) stage where inhibition by the antibiotic D-cycloserine is shown, two molecules of Dalanine (small circles) are converted by an isomerase to the D-forms (small, darker circles), alter which a ligase joins the two D-alanines together to produce a D-alanyl-D-alanine dipeptide.

Structure-based design has been effectively utilized in synthesis of inhibitors of non-proteolytic enzymes. Inhibitors of MurB, an essential bacterial enzyme required for biosynthesis of peptidoglycan, were identified using the X-ray structure of the enzyme for library design. Thiazolidinone inhibitors (8) thus identified are the first examples of small molecule inhibitors of MurB. 

Fig. 12.2 Pathway for the biosynthesis of peptidoglycan in bacterial cells showing the sites of action of cycloserine, glycopeptide and p-lactam antibiotics.

Fosfomycin is one of a few natural products containing a carbon-phosphorus (C— P) bond isolated from Streptomyces fradiae, Streptomyces viridochromogenes, and Streptomyces wedmorensis [73]. It was also isolated from Pseudomonas syringae and Pseudomonas viridiflava [74, 75], Fosfomycin is a highly effective antibiotic of low toxicity clinically utilized for the treatment of lower urinary tract infections [76] as well as methicillin-resistant [77] and vancomycin-resistant [78] strains of S. aureus. Moreover, fosfomycin is effective for the treatment of cephalosporin- and penicillin-resistant Streptococcus pneumonia [79] and ciprofloxacin-resistant E. coli [80], The antimicrobial activity of fosfomycin has been ascribed to the inactivation of UDP-GlcAAc-3-O-enolpyruvyltransferase (MurA), an essential enzyme that catalyzes the first committed step in the biosynthesis of peptidoglycan, the main component of the cell wall, by covalent alkylation of an active site cysteine [81]. 

The biosynthesis of peptidoglycans involves the formation of both UDP-NAG (11.121a) and UDP-NAM (11.121b) as essential intermediates, which then take part in reactions of type (11.119) above. 

Peptidoglycans.—The biosynthesis of the peptidoglycans of bacterial cell walls and the action of penicillin on the biosynthesis of peptidoglycans have been re-viewed. Other reviews have discussed the effects of endogenous and exogenous factors on the primary structures of bacterial peptidoglycans and the com-... 

Isoprenoid lipid carriers are used to convert the hydrophilic nucleotide diphosphate sugars into a form that is able to penetrate the cytoplasmic membrane. It will be recalled that isoprenoid sugar carriers are also used in the biosynthesis of peptidoglycan (p. 14) and LPS (p. 79). In actively growing bacteria there must be sufficient sugar-charged isoprenoid carrier... 

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