Amino penicillanic acid 6-APA

The term / -lactamase denotes an enzyme which catalyzes the hydrolysis of the amide bond in the /3-lactam ring of 6-amino-penicillanic acid (6-APA) or 7-amino-cephalosporanic acid (7-ACA) and of their A-acyl derivatives (2). Such derivatives are commonly referred to as penicillins [Fig. 1 (I) and cephalosporins Fig. 1 (III), (V), and (VII)], respectively. There is no evidence that any bond other than the amide bond in the intact nucleus of penicillin or cephalosporin is broken by the... 

During the same period, Sheehan was working toward a total synthesis of penicillins. In 1958, he announced the synthesis of 6-amino-penicillanic acid (6-APA) and its utility for the preparation of new penicillins by acylation (67, 68). (Almost 10 years earlier, this substance had been postulated to be an intermediate in the biosynthesis of penicillins (69, 70). Prior Japanese literature also contained clear suggestions that it had been formed by enzymatic hydrolysis of benzylpenicillin (71) and in fermentations carried out in the absence of side chain precursors... 

Scheme 19.18 Production of the semisynthetic penicillins. This process takes advantage of large-scale fermentation to obtain penicillin G (61) from microbes in order to establish the requisite stereochemistry at positions 3, 5, and 6 as indicated on 6-APA. An isolated enzyme (Penicillin Acylase) is then used to cleave the phenylacetic acid group off of the 6-position amide in 61. The resulting 6-amino-penicillanic acid (6-APA) can then be readily acylated with any acid chloride under buffered conditions so as to prevent a build-up in acidity during the reaction. Table 19.8 lists some representative semi-synthetic penicillins.

Production of 6-amino penicillanic acid (6-APA) from penicillin G or V by the action of penicillin amidase from E. coli, Bacillus megaterium, or Bovista plumba (Toyo Jozo Inc., Asahi Chemical Industry Co., Ltd., Fujisawa Pharmaceutical Co., Gist-Brocades/DSM, Novo-Nordisk, Pfizer, and others). Annual world production of 6-APA 6000 tons, used for the manufacture of semisynthetic penicillins. 

The role of p-lactam acylases in the manufacturing of semisynthetic cephalosporins and penicillins. In the left pathway, the production of 6-amino penicillanic acid (6-APA) from the fermentation product penicillin G is shown. In the right pathway, the production of 7-aminocephalosporanic acid (7-ACA) from the fermentation product cephalosporin-C is depicted... 

Other amino acids, and some antibiotics, especially the conversion of 6-amino-penicillanic acid (APA) to 7-aminodesacetoxycephalosporanic acid (ADCA), acrylamide, aspartame, citric acid, and niacinamide. 

The widespread use of penicillin eventually led to a clinical problem of penicillin-resistant staphylococci and streptococci. Resistance for the most part involved the penicillin-destroying enzyme, penicillinase, which attacked the beta-lactam structure of the 6-amino-penicillanic acid nucleus (6-APA). 

A number of new derivatives of 6-APA and 7-ACA have been made and evaluated. Of particular interest is 6-(R-a-amino-3-thienylacetamido )penicillanic acid (ll) whose in vitro antibacterial activity is comparable with the clinically useful ampicillin (ill) but is significantly more active in animal protection tests when administered orally. 

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