Cell wall synthesis

Inhibitors of ceil wall synthesis are suitable antibacterial agents because animal, including human, cells lack a cell wall. These agents exert a bactericidal action on growing or multiplying germs. Members of this class include p-lactam antibiotics such as the penicillins and cephalosporins, in addition to bacitracin and vancomycin. 

Penicillins (A). The parent substance of this group is penicillin G (benzylpenicillin). It is 

Penicillins are generally well tolerated with penicillin G, the daily dose can range from approx. 0.6 g i.m. (= 106 international units, 1 Mega IU [MIU]) to 60 g by infusion. The most important adverse effects are due Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

Penicillin G undergoes rapid renal elimination mainly in unchanged form (plasma ty, 0.5 hours). The duration of the effect can be prolonged by  

Use of higher doses, enabling plasma levels to remain above the minimally effective antibacterial concentration. 

The enzyme transpeptidase cross-Unks the peptide chains of adjacent amino-sugar chains. 

Penicillins (A). The parent substance of this group is penicillin G (ben-zylpenidllin]. It is obtained from cultures of mold fungi, originally from Pen-icillium notatum. Penicillin G contains the basic structure common to all penicillins, 6-amino-penicillanic acid (p. 

6-APA), comprised of a thiazolidine and a 4-membered 3-lactam ring, 6-APA itself lacks antibacterial activity. 

Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacteria are in their growth and replication phase, penicillins are bactericidal due to cell wall defects, the bacteria swell and burst. 

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The mechanism of antibacterial activity is through inhibition of gram-positive bacterial cell-wall synthesis thus, the penicillins are most effective against actively multiplying organisms. Because mammalian cells do not have a definitive cell-wall stmcture as do bacteria, the mammalian toxicity of the penicillins is low. Allergic phenomena in patients following sensitization may occur. 

IB 90,000 250 (8) transglycosylase, major transpeptidase of cell elongation essential for cylindrical cell wall synthesis rapid lysis... 

A book (1) and several general reviews (2—4) on P-lactamases have been pubUshed. Based on sequence data, it has been suggested that P-lactamases evolved from the enzymes involved in bacterial cell wall synthesis (5—7). 

In general, penicillins exert thek biological effect, as do the other -lactams, by inhibiting the synthesis of essential structural components of the bacterial cell wall. These components are absent in mammalian cells so that inhibition of the synthesis of the bacterial cell wall stmcture occurs with Htde or no effect on mammalian cell metaboHsm. Additionally, penicillins tend to be kreversible inhibitors of bacterial cell-wall synthesis and are generally bactericidal at concentrations close to thek bacteriostatic levels. Consequently penicillins have become widely used for the treatment of bacterial infections and are regarded as one of the safest and most efficacious classes of antibiotics. 

N. S. Ryder ia C. Nombela, ed.. Microbial Cell Wall Synthesis andMutolysis Elsevier Science PubHshers, Amsterdam, The Netherlands, 1984, pp. 

Several drugs in current medical use are mechanism-based enzyme inactivators. Eor example, the antibiotic penicillin exerts its effects by covalently reacting with an essential serine residue in the active site of glycoprotein peptidase, an enzyme that acts to cross-link the peptidoglycan chains during synthesis of bacterial cell walls (Eigure 14.17). Once cell wall synthesis is blocked, the bacterial cells are very susceptible to rupture by osmotic lysis, and bacterial growth is halted. 

This insertion is accomplished by an enzyme called transpeptidase. -Lactam antibiotics function as substrates for the transpeptidase, thereby establishing selective inhibition of bacterial cell wall synthesis. The structural similarity between -lactam antibiotics and the alanylalanine unit is remarkable as can be seen in Figure 6.8. 

Like penicillins, cephalosporins are (3-lactam antibiotics and interfere with bacterial cell wall synthesis. A very large number of cephalosporins are available for clinical use. They differ in their route of administration and clinical use. 

Vancomycin (Vancocin) acts against susceptible gram-positive bacteria by inhibiting bacterial cell wall synthesis and increasing cell wall permeability. This drug is used in the treatment of serious gram-positive infections that do not respond to treatment with other anti-infectives. It also may be used in treating anti-infective-associated pseudomembranous colitis caused by Clostridium difficile. 

Most aiititubercular drag s are bacteriostatic (slow or retard the growth of bacteria) against the M. tuberculosis bacillus. These dm usually act to inhibit bacterial cell wall synthesis, which slows the multiplication rate of the bacteria. Only isoniazid is bactericidal, with rifampin and streptomycin having some bactericidal activity. 

Topical antibiotics exert a direct local effect on specific microorganisms and may be bactericidal or bacteriostatic. Bacitracin (Baciguent) inhibits the cell wall synthesis. Bacitracin, gentamicin (G-myticin), erythromycin (Emgel), and neomycin are examples of topical antibiotics. These drugp are used to prevent superficial infections in minor cuts, wounds, skin abrasions, and minor burns. Erythromycin is also indicated for treatment of acne vulgaris. 

Solutes must also enter to provide the metabolites for cell wall synthesis and to maintain the osmotic forces necessary to drive enlargement. A restricted supply of water might induce changes in any of these processes. 

Necas O. (1971) Cell wall synthesis in yeast protoplasts. Bacteriol Rev, 35, 149-170. 

Proanthocyanidins Bacteria Ceii coat poiymers Inhibition of cell-associated proteolysis inhibition of cell wall synthesis [76]... 

Although a few mechanisms have so far been proposed to explain the antimicrobial properties exhibited by proanthocyanidins (e.g., inhibition of extracellular enzymes) [86], Jones et al. [83] postulated that their ability to bind bacterial cell coat polymers and their abihty to inhibit cell-associated proteolysis might be considered responsible for the observed activity (Table 1). Accordingly, despite the formation of complexes with cell coat polymers, proanthocyanidins penetrated to the cell wall in sufficient concentration to react with one or more ultra-structural components and to selectively inhibit cell wall synthesis. Decreased proteolysis in these strains may also reflect a reduction of the export of proteases from the cell in the presence of proanthocyanidins [83]. 

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... 

Inhibit bacterial cell-wall synthesis by Streptococci, meningococci,... 

Cell-wall synthesis inhibitors Penicillins Cephalosporins Mon obac tarns Carbapenem Vancomycin Cycloserine... 

The answer is b. (Hardmanr p 1158.) Isoniazid inhibits cell-wall synthesis in mycobacteria. Increasing vitamin B6 levels prevents complications associated with this inhibition, including peripheral neuritis, insomnia, restlessness, muscle twitching, urinary retention, convulsions, and psychosis, without affecting the antimycobacterial activity of INH. 

The answer is a. (Hardman, p 1157. Katzung, p 804J Isoniazid inhibits mycobacterial cell-wall synthesis by inhibiting my colic acid synthesis by a mechanism that is not fully understood. 

The answer is c. (Hardman, pp 1143-1144.) Bacitracin, cycloserine, cephalothin, and vancomycin inhibit cell-wall synthesis and produce bacteria that are susceptible to environmental conditions. Polymyxins disrupt the structural integrity of the cytoplasmic membranes by acting as cationic detergents. On contact with the drug, the permeability of the membrane changes. Polymyxin is often applied in a mixture with bacitracin and/or neomycin for synergistic effects. 

These circumstances became apparent to the authors when they attempted to study the formation of KDO 8-phosphate as catalyzed by purified bacterial extracts. These extracts did not catalyze the formation of KDO 8-phosphate from D-ribose 5-phosphate, but required D-arabinose 5-phosphate as the substrate Heath and Ghalambor29 showed that the KDO 8-phosphate synthetase reaction, observed in Pseudomonas extracts by Levin and Racker, is also catalyzed by extracts from Escherichia coli strains 0 111 B4 and J-5. Rick and Osborn136 showed that the KDO 8-phosphate synthetase from a Salmonella typhimurium mutant conditionally defective in cell-wall synthesis had a KM of 6 mM as compared to a KM of 170 pM for the enzyme from wild-type cells. 

J. L. Strominger, Enzymatic Reactions in Bacterial Cell Wall Synthesis Sensitive to Penicillins, Cephalosporins, and Other Antibacterial Agents , Antibiotics 1967, 1, 705-713. 

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