BIOGENESIS OF ANTIBIOTICS 



65 



mycelial growth ceases, actiiiomycin no 

 longer forms. Although the amount of 

 actinomycin produced is small as compared 

 to the mycelium synthesized, it is believed 

 that the organism synthesizes, in addition 

 to actinomycin itself, a large number of 

 closely related compounds. It has been con- 

 cluded that actinomycin is neither a degrada- 

 tion nor an autolytic product of the cell 

 protein, but that its formation is a result of a 

 side reaction of the assimilating process of 

 metabolism (Martin and J^ampus, 19")()). 

 I'^rommer (lOo?) found that phenylthiourea 

 produces no depression in the respiration of 

 organisms that produce actinomycin. The 

 formation of this antibiotic in certain culture 

 media is inhibited without growth inhibition. 

 Some of the antibiotics, such as strepto- 

 mycin, neomycin, and the tetracyclines, are 

 produced in concentrations of 5 to 10 gm per 

 liter of culture medium. Although the media 

 used for the production of these antibiotics 

 vary greatly in chemical composition, one 

 may assume that they contain about 80 to 

 80 gm per liter of nutrients, mostly carbo- 

 hydrates, lipids, amino acids, proteins, and 

 certain minerals. One may further assume 

 that the organism metabolizes most of those 

 nutrients, thereby converting about 80 per 

 cent of the consumed suljstrate into cell sub- 

 stance. This would give a maximal synthesis 

 of 10 to 2") gm of cell material per liter of 

 medium. One can thus calculate that the 

 antibiotic compounds make up approxi- 

 mately 38 to 40 per cent of the total cell 

 material synthesized. In some cases, the 

 transformation is undoubtedly nuich lower, 

 as in the case of Strcplomijces antihioticns 

 growing in a glutamic acid-glycerol medium. 

 Of the lo gm of nutrients per liter, 10 gm ai'e 

 consumed in 10 to 12 days, giving ].") gm of 

 cell material and 150 mg of actinomycin. The 

 cell synthesis comprises only 10 per cent and 

 antibiotic synthesis only 1 per cent of the 

 nutrients added to the medium, or 1.5 per 

 cent of the nutrients consumed. 



Assuming the correctness of the above 

 calculations, one is led to the inevitable con- 

 clusion that the antibiotic substance is not a 

 mere metabolic intermediate or an ordinary 

 \vaste product of the microbial cell, but that 

 it is a constituent of the living cell proto- 

 plasm, a storage product, or a special by- 

 product. If it were a storage product, the 

 organism should have the capacity to utilize 

 it for its own metabolism, which is not neces- 

 sarily the case, although apparently mecha- 

 nisms exist which bring about the destruc- 

 tion of at least some of the antibiotics if 

 allowed to remain in contact with the living- 

 cells of the organisms producing them. 



These calculations place such antibiotics 

 as streptomycin beyond the scope of an 

 intermediate or a waste product of metabo- 

 lism. Thus the biogenesis of the antibiotic is 

 closely allied to its role in the metabolism of 

 the organism. Since so many different anti- 

 biotics are produced by different organisms, 

 one must postulate a great variety of meta- 

 bolic reactions. Further, since each organism 

 frequently produces more than one antibiotic 

 or several closely related chemical com- 

 pounds, the (juestion arises as to the extent 

 and variety of metabolic reactions involved 

 in the growth of actinomycetes. 



Bu'lock (1900) emphasized the fact that 

 although a single species or a restricted range 

 of i-elated species of microbes is able to 

 produce a great variety of chemical com- 

 poinids, often of great structural complexity, 

 the fundamental chemistry of these organ- 

 isms is based upon a limited gi'oup of reac- 

 tions and compounds and "is i'emarkal)ly 

 uniform throughout most living things." 

 We have thus, on the one hand, a limited 

 variety of basic metabolic pathways; on the 

 other, a seemingly endless variety of second- 

 ary metabolites, of which the antil^iotics 

 represent merely an arbitrary selection. As a 

 result of recent studies on the l)iosynthesis 

 of antibiotics and other natural products, it 

 is possible to demonstrate that certain pre- 



