BIOGENESIS OF ANTIBIOTICS 



67 



"bound" antil)i()tic. Actiiall.v, higher produc- 

 tion of streptomycin may be obtained in the 

 absence of .saU. 



Gwatkin (1954) found that large ([uan- 

 tities of neomycin, sufficient to account for 

 nearly all the antibiotic which later appeared 

 in the medium, had been present in the 

 mycelivnn of the organism pi'oducing this 

 antibiotic (N. fradiae). At a proper pH, the 

 neomycin is released by salt from its com- 

 bination, which was considered to be a neo- 

 mycin-micleic acid complex. This complex 

 was found to be present in the disintegrated 

 cell material. Neomycin foi'med insoluble 

 compounds with ribonucleic and deoxy- 

 I'ibomicleic acids and protamine nucleinate, 

 but not with nucleotides or hydrolyzed 

 nucleic acid. Xeamine, a hydrolytic product 

 of neomycin, did not form any such com- 

 plexes. 



Surikova and Rudakova (1958) compared 

 \'ari()us methods of extraction of strepto- 

 mycin from the mycelium of S. griseus. The 

 most effective method consisted in the 

 acidification of the mycelium with a mineral 

 acid (pH 2.o) and subsequent heating. As 

 much as lo per cent of the streptomycin 

 could thus be extracted, as compared to the 

 amount obtained from the broth. In the case 

 of a soya bean medium, it was possible to ex- 

 tract about 1 ") per cent of the streptomycin. 

 The amount of the antibiotic bound with 

 the mycelium of the organism, as calculated 

 pel' unit weight of mycelium, did not change 

 significantly in the process of fermentation. 



Legator and Gottlieb (19o.3) found that 

 chloramphenicol production reached its peak 

 well after maximal growth had been at- 

 tained. This was particularly true of organic 

 media, a rise in the concentration of the 

 antil)iotic being correlated with an increase 

 in pH and in ammonium ions, and finall,v 

 with a lysis of the mycelium. These investi- 

 gators believed that the antibiotic is not 

 stored within the cells of the organism to any 

 large extent. It is either immediatelv secreted 



into the medium upon production, or is 

 formed from a degradation product. When 

 high concentrations of the antibiotic were 

 added to the medium, no more chloram- 

 phenicol was formed, the concentration 

 needed to arrest further production being 

 e(lui^•alent to the amount normally formed 

 by the cell when no antibiotic was added. 

 Chloramphenicol added at any time during 

 the growth phase of the organism exerts its 

 limiting action on further production, al- 

 though nol on the synthesizin.g al)ility of the 

 cells. 



These data indicate that most antibiotics 

 are formed intracellularly and are i-eleased 

 in the culture UK^dium. It is doubtful that 

 any of the well known antil)iotics are formed 

 extracelhilarly. 



Mechanism of Biosynthesis of Anti- 

 hioties 



On the l)asis of what is known of the 

 chemical structure of antibiotics of actino- 

 mycetes and of the mechanism of their bio- 

 synthesis, Al)raham and Xewton (1960) 

 grouped antil)iotics into three main classes: 

 those dei'iA'al)le from sugars, from amino 

 acids, and fi'om acetate. In the following 

 discussion we have grouped the antibiotics 

 according to this general outline. 



Atitibiotics Derivable from Sugars 



STREPTOMYCIN 



It has been definitely established that 

 some of the nutrients in the medium are 

 important largely for cell growth and others 

 for antibiotic synthesis. This has been stud- 

 ied extensively for penicillin, streptomycin, 

 and the teti'acy<'lines. Agatov and Kazan- 

 skaya (19.')8) hiixe shown that in the growth 

 of streptomycin-producing »S'. griseus, during 

 the first 2 days, histidine and arginine are 

 rapidly utilized and lysine is utilized more 

 slowly; on the third day, rapid utilization of 

 lysine takes place. This is accompaniexl b.v 



