Wall, cell, bacterial, antibiotics acting

All amino acids except glycine exist in these two different isomeric forms but only the L isomers of the a-amino acids are found in proteins, although many D amino acids do occur naturally, for example in certain bacterial cell walls and polypeptide antibiotics. It is difficult to differentiate between the D and the L isomers by chemical methods and when it is necessary to resolve a racemic mixture, an isomer-specific enzyme provides a convenient way to degrade the unwanted isomer, leaving the other isomer intact. Similarly in a particular sample, one isomer may be determined in the presence of the other using an enzyme with a specificity for the isomer under investigation. The other isomer present will not act as a substrate for the enzyme and no enzymic activity will be demonstrated. The enzyme L-amino acid oxidase (EC 1.4.3.2), for example, is an enzyme that shows activity only with L amino acids and will not react with the D amino acids. 

The vancomycin antibiotics act by an intriguing mechanism [137,138]. They interfere with the transglycosylation step of the bacterial peptidoglycan biosynthesis. Vancomycin binds to mucopeptide precursor molecules of the bacterial cell wall, terminating in Lys-D-Ala-D-Ala [139] and thereby preventing the approach of the transglycosylase. 

Beta-lactam antibiotics act on enzymes called penicillin-binding proteins (PBP) near the bacterial cell wall. When beta-lactam antibiotics bind covalently and irreversibly to the PBP, they interfere with the production of cell-wall peptidoglycans, causing cell lysis in hypoosmotic environments. Differences in the spectrum of activity and actions of beta-lactam antibiotics result from their relative affinity for different PBP. 

The three-dimensional structure of the beta-lactam portion of both penicillins and cephalosporins is sufficiently similar to that of D-alanine-D-alanine (see Fig. 2.4), that the transpeptidase enzyme acts upon the drugs instead of the bacterial polypeptide chain. The enzyme becomes covalently attached to the antibiotic and is then unable to carry out its normal functions such that new cell wall material cannot be produced and the dividing bacterium cannot survive. Unfortunately, the penicillinases and cephalosporinases (now known collectively as beta-lactamases) that have evolved to meet the threat posed by the antibiotics act upon the drugs to destroy their beta-lactam rings so that they can no longer inactivate the transpeptidase enzymes. 

The introduction of penicillin into medical practice in 1941, and of streptomycin, chloramphenicol, and the tetracyclines in the following 8 years, opened up a new vista in chemotherapy. Antibiotics were at first regarded with much awe, and a completely new mode of action was predicted for them. In the course of time, though, they have been found to use the established types of receptor. Those antibiotics like penicillin and cephalosporin which prevent the synthesis of bacterial cell-wall have turned out to have an enzyme for receptor (Section 12.i), and this is true of the simpler oxamycin (Section 9.4). Many other antibiotics act on DNA, preventing its replication or transcription such are adriamycin, actinomycin, mitomycin, and bleomycin (Section 4.0). Rifamycin, however, acts on the protein of DNA-primed RNA-polymerase. 

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. 

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. 

Beta-lactam antibiotics are a second great class of antibacterials penicillins, cephalosporins, carbapenems, and monobactams. They act by inhibiting bacterial cell wall synthesis. 

An important molecular target of the B-lactam antibiotics is an enzyme that acts as a transpeptidase in the stepwise polymerization leading to a thickened, strong bacterial cell wall. Several amino acids are present in addition to the terminal -alanyl- -alanyl unit which the Strominger hypothesis suggests has the same overall shape and reactivity as... 

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. 

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

Examples of enzyme inhibitors that can be used as drugs Enzyme inhibitors can be used as drugs, inhibiting either intracellular or extracellular reactions. For example, the p-lactam antibiotics, such as penicillin and amoxicillin, act by inhibiting one or more of the enzymes of bacterial cell wall synthesis. 

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). 

Polymyxin B. Polymyxin antibiotics are cationic compounds that are attracted to negatively charged phospholipids in the bacterial cell membrane. These drugs penetrate and disrupt the architecture and integrity of the surface membrane. Essentially, polymyxins act as detergents that break apart the phospholipid bilayer, which creates gaps in the bacterial cell wall, leading to the subsequent destruction of the bacteria.31... 

Antibacterial antibiotics normally act by either making the plasma membrane of bacteria more permeable to essential ions and other small molecules by iono-phoric action or by inhibiting cell wall synthesis (see section 7.2.2). Those compounds that act on the plasma membrane also have the ability to penetrate the cell wall structure (Appendix 3). In both cases, the net result is a loss in the integrity of the bacterial cell envelope, which leads to irreversible cell damage and death. 

C. Mechanisms of Action and Resistance Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps (Figure 43 2) (1) binding of the drug to specific receptors (penicillin-binding proteins PBPs) located in the bacterial cytoplasmic membrane (2) inhibition of transpeptidase enzymes that act to cross-link linear peptido-glycan chains which form part of the cell wall and (3) activation of autolytic enzymes that cause lesions in the bacterial cell wall. 

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