Penicillins and Cephalosporins BT - Biosynthesis

Abstract

The penicillins have the general structure (I) and are N-acyl derivatives of 6-aminopenicillanic acid (6-APA, II). During the early chemical work on penicillin it was found that the substance being studied in Oxford differed in its acyl side-chain from that studied in the U.S.A. (Clarke, Johnson and Robinson, 1949; Abraham, 1949). In the former (2-pentenylpenicillin) R was CH3CH2CH =CH · CH2 and in the latter (benzylpenicillin) R was C6H5CH2. Subsequent work showed that many different penicillins could be produced byPenicillium chrysogenum by the addition of appropriate side-chain precursors to fermentation media (Behrens et al., 1948; Thorn and Johnson, 1950). Most of the precursors which were effective in this way were monosubstituted acetic acids or their derivatives (R · CH2CO2H) in which R was a relatively non-polar aliphatic or aromatic grouping. Later, certain species of Cephalosporium and members of the genus Emericellopsis were shown to produce a penicillin with a zwitterionic side-chain derived from D-α-aminoadipic acid (Abraham, 1962). This substance, which was first named cephalosporin N or synnematin B and later penicillin N, has also been reported to be produced by a Streptomyces sp. (Miller, Stapley and Charet, 1962) and by Paecilomyces persicinus (Pisano et al., 1960). Following the discovery of penicillin N, it was found that 6-aminopenicillanic acid (II) (Batchelor et al., 1959) and isopenicillin N, whose side-chain (RCO in I) is derived from L-α-aminoadipic acid (Flynn et al., 1962; Cole and Batchelor, 1963), can be produced in significant amounts byP. chrysogenum in fermentations to which no side-chain precursor is added.