Bacteria cell wall synthesis inhibitors

Specific damage to bacteria is particularly practicable when a substance interferes with a metabolic process that occurs in bacterial but not in host cells. Clearly this applies to inhibitors of cell wall synthesis, because human and animal cells lack a cell wall. The points of attack of antibacterial agents are schematically illustrated in a grossly simplified bacterial cell, as depicted in (2). 

Other inhibitors of cell wall synthesis. Bacitracin and vancomycin interfere with the transport of pepti-doglycans through the cytoplasmic membrane and are active only against gram-positive bacteria. Bacitracin is a polypeptide mixture, markedly nephrotoxic and used only topically. Vancomycin is a glycopeptide and the drug of choice for the (oral) treatment of bowel inflammations occurring as a complication of antibiotic therapy (pseudomembranous enterocolitis caused by Clostridium difficile), it is not absorbed. 

ANTIBIOTICS 0-LACTAMASE INHIBITORS. The antibacterial effectiveness of penicillins, cephalosporins, and other 0-lactam antibiotics depends on selective acylation and consequently, inactivation, of transpeptidases involved in bacterial cell wall synthesis. This acylating ability is a result of the reactivity of the 0-lactam ring (1). Bacteria that are resistant to 0-lactam antibiotics often produce enzymes called 0-lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the 0-lactam... 

Inhibitors are substances that tend to decrease the rate of an enzyme-catalysed reaction. Although some act on the substrate, the discussion here will be restricted to those inhibitors which combine directly with the enzyme. Inhibitors have many uses, not only in the determination of the characteristics of enzymes, but also in aiding research into metabolic pathways where an inhibited enzyme will allow metabolites to build up so that they are present in detectable levels. Another important use is in the control of infection where drugs such as sulphanilamides competitively inhibit the synthesis of tetrahydrofolates which are vitamins essential to the growth of some bacteria. Many antibiotics are inhibitors of bacterial protein synthesis (e.g. tetracyclin) and cell-wall synthesis (e.g. penicillin). 

Two other irreversible inhibitors are penicillin G (4.18), a /3-lactam antibiotic, and orlistat (Xenical or Alii, 4.19), an antiobesity drug (Figure 4.19). Penicillin G inhibits cell wall synthesis in bacteria, while orlistat inhibits the breakdown of fats in the small intestine.16 Both drugs contain acid derivatives in a strained four-membered ring. Nucleophiles in the active sites of the inhibited enzymes attack the reactive carbonyl groups and open the strained ring in an energetically favorable, irreversible process. 

Bacterial infections are treated with antibiotics. There are many antibiotics available, but they fall into three major groups based on their mode of action inhibitors of bacterial nucleic acid synthesis inhibitors of cell wall synthesis and inhibition of bacterial protein synthesis. Resistance of bacteria to commonly-used antibiotics has become a major problem necessitating the development of new antibiotics. Tuberculosis infection is difficult to treat and requires a combination of at least three different antibiotics. 

Antibiotic carbapenem active against many aerobic and anaerobic bacteria, including penicillinase-producing organisms a bactericidal inhibitor of cell wall synthesis. Used with cilastatin (which inhibits metabolism by renal dehydropeptidases). Tox allergy (partial cross-reactivity with penicillins), seizures (overdose). Meropenem is similar but does not require cilastatin. 

Vancomycin is bactericidal to most susceptible bacteria at concentrations near its minimum inhibitory concentration (MIC) and is an inhibitor of bacterial cell wall peptidoglycan synthesis, although at a site different from that of j3-lactam antibiotics (Chapter 9). 

Cell walls are biochemically rather inert with reduced digestibility to many organisms because of their complex cellulose, pectin, and lignin molecules. Callose and lignin are often accumulated at the site of infection or wounding (6,7) and form a penetration barrier. Synthesis of inhibitory proteins (e.g., lectins, protease inhibitors) or enzymes (e.g., chitinase, lysozyme, hydrolases, nucleases) that could degrade microbial cell walls or other microbial constituents would be protective, as well as synthesis of peroxidase and phe-nolase, which could help inactivate phytotoxins produced by many bacteria and fungi. These proteins are either stored in the vacuole... 

The antibiotic penicillin is a transition state analog that binds very tightly to gly-copeptidyl transferase, an enzyme required by bacteria for synthesis of the cell wall (Fig. 8.18). Glycopeptidyl transferase catalyzes a partial reaction with penicillin that covalently attaches penicillin to its own active site serine. The reaction is favored by the strong resemblance between the peptide bond in the p-lactam ring of penicillin and the transition state complex of the natural transpeptidation reaction. Active site inhibitors such as penicillin that undergo partial reaction to form irreversible inhibitors in the active site are sometimes termed suicide inhibitors. ... 

---