Benzylpenicillin, discovery

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The major penicillin produced by P. chrysogenum in submerged culture was benzylpenicillin (PenG) (Figure 4), which was rather unstable under acid conditions and also deactivated by P-lactamases. However, the discovery of 6-aminopenicillanic acid (6-APA) also produced by P. chrysogenum, led to the preparation of new semisynthetic derivatives with improved stability e.g. methicillin, ampicillin and amoxycillin (Figure... 

The compound (which had a dihydrothiazine ring fused to the P-lactam core) showed resistance to P-lactamases and was less toxic than benzylpenicillin. The discovery that the basic building block, namely 7-aminocephalosporanic acid (7-ACA), could be synthesised, led to the preparation of numerous cephalosporin derivatives eg cephalothin, cephaloglycin (orally active), cefaclor and cefuroxime (Figure 7). 

A second method of producing 6-APA came with the discovery that certain microorganisms produce enzymes, penicillin amidases (acylases), which catalyse the removal of the side-chain from benzylpenicillin (Fig. 10. IB). 

The years between 1940 and 1959 have been justly called the golden era of antibiotic discovery. During this period every important class of antibacterial antibiotic now known was recognized (Table III). Indeed, many specific drugs (e.g., benzylpenicillin, streptomycin, oxytetracycline, chloramphenicol, neomycin, and erythromycin) which presently occupy major places in therapeutic practice were discovered during that period. 

Further studies of a-substituted benzylpenicillins led to the independent discovery by Pfizer and Beecham chemists of carbenicillin (< -car-boxybenzylpenicillin) (Figure 19) (89, 90), in which the gram-negative spectrum is extended still further (to Pseudomonas aeruginosa and the ampicillin-insensitive indole-positive Proteus species). 

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