Bacterial cell wall biosynthesis inhibition

Vancomycin (18) analogs Anti-bacterial Cell wall biosynthesis Inhibition Princeton University... 

Phosphomycin, introduced in 1972, inhibits enolpyruvial transferase, an enzyme catalyzing an early step in bacterial cell wall biosynthesis. Inhibition results in reduced synthesis of peptidoglycan, an important component in the bacterial cell wall. Phosphomycin is bactericidal against Escherichia coii and Enterobacter faecaiis infections. 

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... 

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... 

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 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. 

A variety of penicillins have been produced by the fermentation of Penidl-lium chrysogenum in the presence of different nutrients. Penicillin G (ben-zylpenicilbn see Figure 1) predominates when the culture medium is rich in phenylacetic acid, whereas the incorporation of phenoxyacetic acid favors penicillin V (phenoxymethylpenicillin). Semisynthetic penicillins, such as ampicillin and amoxicillin, are prepared by replacing the aromatic side chain of biosynthetically derived penicillins with other chemical groups. All peni-cilhns are j8-lactam (see Figure 2) antibiotics and have the same mechanism of action They inhibit bacterial cell wall biosynthesis. 

The molecular targets for the antibacterial activity of the penicillin and related j8-lactam antibiotics such as the cephalosporins are a group of bacterial enzymes known as penicillin-binding proteins (PBPs). The PBPs are essential to the final stages of bacterial cell wall biosynthesis. Penicillin and other j8-lactam antibiotics inhibit PBPs, thereby inhibiting bacterial cell wall biosynthesis, which eventually results in bacterial cell lysis. (Vancomycin and cycloserine are nonpenicillin antibiotics that also inhibit bacterial cell wall biosynthesis through other mechanisms.)... 

Penicillin is an antibiotic that works by inhibiting the transpeptidase enzyme involved in bacterial cell wall biosynthesis (Figure 16.21). 

C3H7O4P, Mr 138.06, crystals, mp. 94 °C, [aj -14° (HjO) soluble in water, antibiotic with a wide spectrum of activity produced by streptomycetes and pseudomonads. For the unusual biosynthesis, see Lit.. F. prevents the biosynthesis of bacterial cell walls by inhibiting pyruvate-uridine diphospho-A -acetylglucos-amine transferase (EC 2.5.1.7). The calcium and ammonium salts are used in therapy. F. achieves high urine levels after oral administration and single doses are used for urinary tract infections. 

Ribosylation of isopropylideneuridine and subsequent manipulations led to the synthesis of 170 (R = H), which constitutes a part-structure of the liposidomycin class of antibiotics. The two isomers of 170 (R = CH2OH) were also prepared in synthetic sequences that involved ribosylation of D-allofuranose and L-talofuranose derivatives at 0-5, with introduction of uracil at a late stage. Molecular modelling was carried out of both liposidomycins and tunicamycin with the UDP-iV-acetylmuramic acid-pentapeptide that is the substrate for the enzyme (translocase) in bacterial cell wall biosynthesis that the antibiotics inhibit, and, in accordance with the predictions, only the 5-isomer of 170 (R = CH2OH) was a good inhibitor. ... 

The antibacterial activity of BLAs is due to the inhibition of transpeptidase enzymes which are involved in bacterial cell wall biosynthesis. The transpeptidases or PBPs catalyze peptidoglycan cross-linking. 

Also included in Volume 3 is a report (Chapter 5) written for the nonmedical scientist describing the clinical uses of the compounds that result from these efforts. The concluding chapters of Volume 3 review two new subjects that are currently at the forefront of p-lactam research. The first of these. Chapter 6, discusses the events that occur in the bacterial cells between cell wall biosynthesis inhibition and cell lysis. It addresses the problem of penicillin-tolerant strains that have the ability to survive in the presence of large amounts of p-lactam antibiotics. The last chapter (7) again turns to a newly discovered class of antibacterial P-lactam natural products. These newly discovered monocyclic compounds, called monobactams, appear to have clinical utility. 

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