Peptidoglycan inhibition

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]. 

Bacterial cell wall j3-Lactams Glyoopeptides Cycloserine Isoniazid Ethambutol Inhibit peptidoglycan synthesis Inhibit peptidoglycan synthesis Inhibits peptidoglycan synthesis Inhibits mycolic acid synthesis Inhibits arabinogalactan synthesis None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells... 

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.

Fosfomycin inhibits pyruvil transferase, which is an enzyme involved in peptidoglycan synthesis. Two mechanisms of acquired resistance have been described for fosfomycin (Davies 1994). 

Catechins Bacteria Cell wall peptidoglycan 8-lactams Inhibition of penicillinase activity [67]... 

Mode of action Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls bacteria usually lyse from ongoing autolytic enzyme activity... 

Exit of the virus from the cell occurs as a result of cell lysis. The phage codes for a lytic enzyme, the T4 lysozyme, which causes an attack on the peptidoglycan of the host cell. The burst size of the virus (the average number of phage particies per cell) depends upon how rapidly lysis occurs. If lysis occurs early, then a smaller burst size occurs, whereas slower lysis leads to a higher burst size. The wild type phage exhibits the phenomenon of lysis inhibition, and therefore has a large burst size, but rapid lysis mutants, in which lysis occurs early, show smaller burst sizes. 

Friulimicins - antimicrobial peptides that inhibit peptidoglycan synthesis... 

The pathway from simple molecules to the peptidoglycan of the bacterial cell wall is lengthy and complex. Many of the details are well known but need not concern us here. Suffice it to say that long carbohydrate chains are synthesized, subsequently decorated with shorter amino acid chains, and these are finally cross-linked to provide a strong strnctnre. It is this final cross-linking step that is inhibited by the p-lactam antibiotics. The consequence is that cell wall biosynthesis cannot be completed and cell death ensnes. Again, the mammalian host carries out no similar reactions so that similar consequences do not ensne for the host orgaiusm. 

Aretz W, Meiwes J, Seibert Q Vobis Ci Wink J. (2000) Frinlimicins novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes Friuliensis sp nov. J Antibiot 53 807-815. 

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). 

For example, Escherichia coli have six PBP. PBP-la and -lb, which are transpepfidases, are involved in the synthesis of peptidoglycan. PBP-2 is necessary for supporting the rodshaped form of bacteria. Selective inhibition of this enzyme causes production of other non-rod-shaped forms of bacteria, which eventually undergo lysis. PBP-3 is necessary to form the partition during division. Selective inhibition of this enzyme leads to the formation of a fibrous form of bacteria containing many units of rod-shaped bacteria unable to separate one from another, which results in their death. Various beta-lactam antibiotics have a selective affinity to one or a few PBP. Inactivation of certain PBP (PBP-la, -lb, -2, or -3) causes cell death. Unlike these, inactivaition of low-molecular PBP (PBP-4, -5, and -6) is not lethal to bacteria. 

Bacitracin is a bactericidal drug that inhibits the formation of linear peptidoglycan chains, which are the main component of bacterial cell membranes. Most Gram-positive bacteria,... 

When grouped on the basis of similarities in their chemical structure, most antibiotics fall into the categories listed in Table 1.17. S-Lactams, which include penicillins and cephalosporins, exhibit a characteristic /i-lactam core ring structure (a four-atom cyclic amide) (Figure 1.14). They induce their bacteriocidal activity by inhibiting the synthesis of peptidoglycan, an essential component of the bacterial cell wall. 

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. 

D) Inhibition of synthesis of peptidoglycan subunits in bacterial cell walls... 

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