Penicillins, development expansion

The enzymatic ring expansion is neither complete nor selective, necessitating product isolation via chromatography in a simulated moving bed system. Because adipyl-7-ADCA rather than G-7-ADCA is produced, a new enzyme, adipyl-7-ADCA acylase, was developed to remove the side chain from adipyl-7-ADCA [132, 133], as the latter is not a substrate for penicillin G acylase. 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

About a decade ago 6-APA and 7-ADCA were mainly produced by chemical deacylation of penicillin G, penicillin V or phenylacetyl 7-ADCA, the last of which was derived from chemical ring expansion of oxidized penicillin G. As a result of the fact that these processes were rather complex and employed hazardous reagents, for example pyridine, phosphorus pentachloride, nitrosyl chloride and dichlorome-thane, alternative processes have been developed. Penicillin amidases (E. C. 3.5.1.11) catalyze the hydrolysis of the linear amide bond in penicillin molecules producing both the P-lactam nucleus, 6-APA and the corresponding side chain without affecting the P-lactam amide bond in the four-membered ring. Based on their substrate specificity the penicillin amidases are grouped into three classes[591 ... 

One area that illustrates the power of metabolic engineering is the development of alternative routes for the production of 7-amino cephalosporanic acid (7-ACA) and 7-amino deacetoxycephalosporanic acid (7-ADCA), which serves as precursors for the production of semisynthetic cephalosporins. Until recently the sole route for 7-ADCA was by chemical ring expansion of 6-amino peniciUanic acid (6-APA), which can be derived from penicilUns. Thus, many semisynthetic cephalosporins were traditionally derived from penicillin produced by fermentation. With the high potential of -lactam production by P. chrysogenum, it is of interest to engineer this organism to produce the cephalosporins directly by fermentation. 

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