Antibiotics pencillins

Beta-lactam antibiotics (pencillins, cephalosporins, and carbapenems) are excreted by the kidneys and hence the kidneys are targets of toxicity. These drugs can cause interstitial nephritis, tubular necrosis, and allergic angitis. Beta-lactams behave like haptens which are then... 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

The most toxic antibiotics were altemaric acid, gliotoxin, glutinosin and mycophenolic acid, and the least toxic were griseofulvin, pencillin and streptomycin. 

A review of the chromatographic behavior of 90 penicillin and cephalspor-ins and their correlation to hydrophobicity has been published [339]. The current state of chromatographic methods submitted to the USP for com- plex antibiotics has been reviewed [340], A comparison has been made between poly(styrene-divinylbenzene) stationary phases and silica-based re-versed-phase sorbents for analysis of erthromycin and minocycline, and it was concluded that the nonsilica-based packings are more stable and ] reproducible [341]. The comparative retentions of ampicillin, amoxicillin,] and pencillin G was determined on Ci8, cyanopropyl-silica and poly(sty- rene-divinylbenzene), and nonbonded silica [342]. 

Several complex antibiotics are prepared by whole-cell fermentations. Examples are the pencillin antibiotics in which the side chain can be removed and replaced with a synthetic one to enhance activity or stability. Other examples include the macrolide antiobiotics, such as avermectin (56) and erythromycin (57), in which the organism uses an enzyme cassette to build up the seco-chain before cyclization. 

The penicillins, from the fungus Penicillium chryso-genum, are the oldest and most widely used antibiotics. They are formed through stepwise build-up from a tripeptide (ACV) derived from a-Amino adipic acid, cysteine, and valine. Successive oxidation steps form the p-lactam and close the thiazolidine ring to form isopenicillin N. Action of an acyltransferase then yields penicillin G (Fig. 47). Alternatively, hydrolysis of isopenicillin N (or penicillin G) yields 6-aminopenicillanic acid, a key precursor for the wide range of semisynthetic pencillins used therapeutically. 

Adsorption is a simple and straightforward route for biocatalyst immobilization which offers unique advantages over soluble enzymes, such as enhanced activity, increased selectivity, improved stability and reusability. For example, Assemblase, the commercial name of immobilized pencillin-G acylase from E. coli, has been used by industry for manufacture of the semi-synthetic p-lactam antibiotic cephalexin. ... 

Rgure 6.8 Pencillins are similar to the bacterial pepHdaglycan terminal alanylalanine moiety. Because of this simOarity, the enzyme transpe( dase recognizes -lactam antibiotics as substrate. As a result of this the p-lactam is incorporated in the pejptide chain thereby ntaKIng peptide-peptide cross-linking impossible. The occurrence of this phenomenon stops the construction of the bacterial cell wall. 

In acidic media the picture is different. Cationic (CTAB) and a non-ionic surfactant (Ci 2 E23) reduced the degradation of several penicillins by a factor of 4 to 12, while an anionic surfactant (NaLS) increased the rate [141]. In all cases the rate constants first increased or decreased rapidly and then approached a constant value above the solubilizer CMC. In contrast to the penicillins, the acid degradation of cefazolin, a relatively acid-unstable cephalosporin, was not influenced by the presence of any of the surfactants, suggesting that this antibiotic is not sufficiently bound to any of the surfactant micelles. The log P values for the affected penicillins (at pH 2.1) are in the range 2.7 (propicillin) to 1.70 (penicillin G) while that of cefazolin is 0.39. It is fairly clear that stabilization of the pencillins is the result of the decreased hydrogen ion activity in the vicinity of the cationic head groups of the micelles. Results for propicillin are shown in Fig. 11.22. 

In the absence of greater understanding of the mode of action of the -lactam antibiotics, the generation of structure-activity data has remained one of trial and error. Cycloaddition of acetylenes to the azide of 7-acylamido-3-azidomethylcephalosporanic acids afforded a series of 3-(l,2,3-triazol-l-ylmethyl)cephalosporanic acids while the syntheses of 7-mandeloylaminocephalosporins, 6-thioacylamino-, a-sulpho-, 6-ami-dino-, cyanoamidino-, and levomycetin adipinyl-pencillins have been described in publications. 

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