CHEMOTHERAPEUTIC AGENTS 153 



properties and ability to metabolize various substances, and 

 also a preference for aerobic growth) with other species 

 growing in the presence of penicillin. By studying whether 

 the development of resistance is accompanied by overall 

 changes in the metabolism of the organism, it may be 

 possible to gain valuable information concerning the mode 

 of action of the agent being considered, and furthermore, 

 if resistance to other drugs is acquired simultaneously, i.e. 

 cross resistance, it is conceivable that the biological effects 

 of all these substances is explicable in the same terms [see 31]. 

 Another as yet unexplained observation that penicillin inter- 

 feres with amino-acid metabolism concerns an unidentified 

 Gram-negative organism which when growing on L-leucyl- 

 glycine in a mineral salt medium was relatively insensitive to 

 penicillin. Leucine and glycine, either singly or together, 

 also supported growth, but in the presence of uncombined 

 glycine the organism was very sensitive to penicillin (i to 

 10 units/ml.) [23]. 



The reports that the training of Staph, aureus to a high 

 degree of resistance to penicillin resulted in a loss of Gram- 

 positive staining properties could be taken to indicate that 

 the biological effects of penicillin were the outcome of 

 primary disturbances in nucleotide metabolism. In normal 

 cultures of Staph, aureus the rate of cell growth appears to 

 be controlled by the amount of pentose nucleic acid in the 

 cells, and the cellular concentration of soluble nucleotides 

 is inversely proportional to the rate of PNA synthesis [17]. If 

 penicillin is added to a culture in the log phase of growth, 

 then before there is any visible change in the growth-rate, 

 the concentration of soluble nucleotides increases and the 

 ratio of soluble nucleotides to total nucleic acid soon changes 

 from o-i to 0-2 (Fig. 10.2). The percentage by weight of 

 nucleic acid at first appears to increase, not because synthesis 

 is stimulated but because there is a decrease in the rate of 

 synthesis of some other substances (protein?) contributing 

 to the dry weight of the cell. Though large amounts of 

 nucleic acid are normally present in young cells, penicillin 

 causes their concentration to fall rapidly to the low value 

 characteristic of old cells in the stationary phase of growth, 



