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1. The reaction of cephalosporins with ammonia, amino acids and other simple amino compounds in weakly alkaline aqueous solutions yields labile compounds with lambda(max.) 230nm. The reaction of deacetyl- and deacetoxy-cephalosporins under similar conditions yields compounds with lambda(max.) 260nm. 2. Hydrolysis with a beta-lactamase results in the formation of compounds with lambda(max.) 230nm from deacetylcephalosporins and cephalosporins, but not from deacetoxycephalosporins. 3. These different compounds decompose to give penaldates and penamaldates derived from the side chain and the carbon atoms of the beta-lactam ring. 4. Derivatives similar to those obtained with simple amino compounds appear to be formed when cephalosporins and their analogues react with lysine polymers. 5. Some of the chemical and physical properties of the various derivatives have been studied and tentative structures for them are proposed. 6. Possible implications of the results in relation to the immunological properties of the cephalosporins are discussed.

1. The production of penicillin N and cephalosporin C by two mutants of a Cephalosporium sp. has been studied with cultures grown in a chemically defined medium and with suspensions of washed mycelium in water or a buffered salt solution. 2. Antibiotic synthesis began at an early stage of growth and its rate per unit weight of mycelium appeared to pass its maximum as morphological changes were occurring in young hyphae. This rate subsequently declined, but rapid production could continue after net growth had ceased. 3. In a series of shake-flask fermentations in the growth medium, increases in the yield of penicillin N above the mean were correlated with much smaller increases in the yield of cephalosporin C and vice versa. 4. In suspensions of washed mycelium, moderate decreases in the efficiency of aeration increased the yield of penicillin N and decreased that of cephalosporin C. A similar result normally followed the addition of methionine to the suspension fluid, and in both cases there was usually an increase in the yield of the two antibiotics combined. 5. The apparent intracellular concentrations of the antibiotics were much lower than those attained extracellularly and also much lower than those of most of the amino acids in the intracellular pool. No detectable amount of [(14)C]penicillin N added to the extracellular fluid was found to enter the mycelium. 6. Very small amounts of peptide material whose behaviour was similar to that of the sulphonic acid of delta-(alpha-amino-adipoyl)cysteinylvaline on paper electrophoresis at pH1.8 were found in extracts of the mycelium that had been oxidized with performic acid. 6-Aminopenicillanic acid and 7-aminocephalosporanic acid were not detected. 7. Ultrasonic treatment of the mycelium resulted in rapid fragmentation of mycelial chains, rupture of many individual cells, and the liberation of amino acids and other substances into the medium. 8. Ultrasonically treated preparations synthesized penicillin N and cephalosporin C rapidly after a lag of 12hr. Antibiotic synthesis was accompanied by the growth of hyphae from swollen mycelial fragments and by the re-establishment of permeability barriers resulting in the uptake of amino acids from the medium.

Abraham & Newton (1956) showed that cephalosporin C was highly resistant to hydrolysis by purified penicillinase from BaciUu8 cereus (strain NRRL 569; see Pollock, 1959, 1960) but was a competitive inhibitor of the action of this penicillinase on benzylpenicillin. More recently, however, cephalosporin C was reported to have no significant inhibitory action on the hydrolysis of benzylpenicillin by penicillinase from a strain of Staphylococcus aureus (Abraham & Newton, 1961 a). Rolinson, Stevens, Batchelor, Wood & Chain (1960) reported that 2,6-dimethoxyphenylpenicillin was a competitive inhibitor of penicillinase from B. cereus, but not of penicillinase from Staph. aureus. These findings suggested that penicillinase from B. cereus and penicillinase from Staph. aureus differed with respect to structural features which influenced the combination of enzyme and substrate. They also drew attention to the fact that the affinity for penicillinase of a member of the cephalosporin C or penicillin family might partly determine the rate of enzymic hydrolysis of the substance in the concentration at which it was used as an antibacterial agent. The results of further experiments in this field are given here. The substances studied were N-acyl derivatives of 7-aminocephalosporanic acid which has structure (I; R = H, R' = CH3 Co00)

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