Bacterial cell wall biosynthesis

Antibiotics have a wide diversity of chemical stmctures and range ia molecular weight from neat 100 to over 13,000. Most of the antibiotics fall iato broad stmcture families. Because of the wide diversity and complexity of chemical stmctures, a chemical classification scheme for all antibiotics has been difficult. The most comprehensive scheme may be found ia reference 12. Another method of classifyiag antibiotics is by mechanism of action (5). However, the modes of action of many antibiotics are stiU unknown and some have mixed modes of action. Usually within a stmcture family, the general mechanism of action is the same. For example, of the 3-lactams having antibacterial activity, all appear to inhibit bacterial cell wall biosynthesis. 

P-Lactams. AH 3-lactams are chemically characterized by having a 3-lactam ring. Substmcture groups are the penicillins, cephalosporias, carbapenems, monobactams, nocardicias, and clavulanic acid. Commercially this family is the most important group of antibiotics used to control bacterial infections. The 3-lactams act by inhibition of bacterial cell wall biosynthesis. 

Studies on the mode of action of the penicillins in inhibiting bacterial cell-wall biosynthesis suggest that the members of this class of antibiotics (including the closely related cephalosporins) are conformationally restricted substrate analogs... 

Tipper D.J. (1988) Antibiotic Inhibitors cf Bacterial Cell Wall Biosynthesis, 2nd edn. Oxford Pergamon Press. 

The antibiotic activity of certain (3-lactams depends largely on their interaction with two different groups of bacterial enzymes. (3-Lactams, like the penicillins and cephalosporins, inhibit the DD-peptidases/transpeptidases that are responsible for the final step of bacterial cell wall biosynthesis.63 Unfortunately, they are themselves destroyed by the [3-lactamases,64 which thereby provide much of the resistance to these antibiotics. Class A, C, and D [3-lactamases and DD-peptidases all have a conserved serine residue in the active site whose hydroxyl group is the primary nucleophile that attacks the substrate carbonyl. Catalysis in both cases involves a double-displacement reaction with the transient formation of an acyl-enzyme intermediate. The major distinction between [3-lactamases and their evolutionary parents the DD-peptidase residues is the lifetime of the acyl-enzyme it is short in (3-lactamases and long in the DD-peptidases.65-67... 

Examples of successful natural product screens directed against proven targets include screens designed to look for inhibitors of bacterial cell wall biosynthesis. These screens were established once it became clear... 

Bacitracin (Fig. 4) is a cyclic peptide antibiotic. The lipid II molecule involved in the bacterial cell wall biosynthesis has a C55 isoprenyl pyrophosphate moiety that must be dephosphorylated so that it can reparticipate in another round of lipid II transfer. Bacitracin binds to the isoprenyl pyrophosphate and prevents the dephosphorylation which, in turn, blocks cell wall growth by interfering with the release of the muropeptide subunits to the outside of the bacterial cell membrane. Bacitracin inhibits similar reactions in eukaryotic cells. So, it is systemically toxic but is an effective and widely used topical antibiotic. 

Antibiotics that inhibit bacterial cell wall biosynthesis... 

The thiopyrano[4,3-c]pyrazole 206 has been found to be a good inhibitor of bacterial cell wall biosynthesis <2003BML2591>. 

Both the cephalosporins and the penicillins owe their antibacterial action to their ability to block bacterial cell-wall biosynthesis. Cephalosporin C is less active than the penicillins, but is less susceptible to enzymatic destruction by /3-lactamases, which are enzymes that cleave the lactam ring. In fact, the so-called resistance of staph bacteria to penicillins is attributed to the propagation of strains that produce /3-lactamase. Numerous semisynthetic penicillins and cephalosporins have been made in the hope of finding new broad-spectrum antibiotics with high activity but with greater /3-lactam stability. Several of these are in clinical use. 

TOTAL SYNTHESIS OF LIPID I AND LIPID II LATE-STAGE INTERMEDIATES UTILIZED IN BACTERIAL CELL WALL BIOSYNTHESIS... 

In summary, we were able to develop a chemically robust synthetic route to lipid I, the penultimate intermediate utilized in bacterial cell wall biosynthesis. The identification of a method for stereoselective introduction of the anomeric phosphate and a protocol to enable diphosphate coupling were pivotal to our success and ultimately provided the precedent for our chemical synthesis of lipid II detailed in the sections that follow. 

Stewart GC. Taking shape control of bacterial cell wall biosynthesis. Mol Microbiol. 2005 57 1177-1181. 

As mentioned in the previous section, enzymes involved in bacterial cell wall biosynthesis are being studied with renewed interest. Among these enzymes is... 

Figure 11 Sequential murein biosynthetic pathway, the early steps of the bacterial cell wall biosynthesis.

J Trias, Z Yuan. Mining bacterial cell wall biosynthesis with new tools multitarget screens. Drug Res Updates 2 358-362, 1999. 

The three-step mechanism of serine enzyme action is usually described as in Equation (1) . Even though the enzyme is recovered in the end, the deacylation step remains slow enough to lead to inhibition of the bacterial cell wall biosynthesis, resulting ultimately in cell lysis by activation of endogenous autolytic mechanisms . 

This can be achieved in a variety of ways. For instance, it is possible to inhibit an essential pathway in the pathogen that does not exist in the host. o-Cycloserine (1) (Fig. 17.1), for example, inhibits alanine race-mase, an enzyme involved in bacterial cell wall biosynthesis and not found in humans (8, 9). D-Cycloserine is active against a broad spectrum of both gram-positive and gramnegative bacteria (10), but plays its major role in the treatment of tuberculosis (11). Conversely, even if both host and pathogen contain the same enzymes, it may be possi-... 

The tetracyclines were discovered towards the end of the 1940 s (structure of oxytetracycline shown in Figure 5), They have a broader spectrum of activity than the early penicillins. In addition effects on bacteria are different. The penicillins are bactericidal whereas the tetracyclines are bacteriostatic, reflecting differing modes of action. Tetracyclines disrupt protein synthesis by binding to the bacterial ribosome whilst the P-lactams inhibit bacterial cell wall biosynthesis. During the 60 s, 70 s and early 80 s, tetracycline-based products made the biggest commercial impact in the animal health industry. 

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