BIOGENESIS OF ANTIBIOTICS 



75 



lows. According to the st met are of its 

 molecule, a propionyl unit is found to repeat 

 itself regularly. The structure of other macro- 

 lides suggests that both acetyl and pro- 

 pionyl residues take part in the condensation 

 process. The macrolides were said to be 

 built up 1)3' a mechanism similar to that by 

 which the long-chain fatty acids are syn- 

 thesized, i.e., by condensation of coenzyme- 

 activated acetyl residues or propionyl resi- 

 dues to jjolyketo acids, which ar(^ then re- 

 duced. 



TETRACYCLINES 



*S. aureofaciens was found (AlcCormick 

 ct a/., 19o9) to produce 2 gm of chlortetra- 

 cycline per liter of media of simple chemical 

 composition. When washed rvW inoculum 

 was previously grown in a corn steep me- 

 dium, the yield increased to 4 gm. With 

 glycerol as a source of carbon and ammonium 

 ion as a source of nitrogen, the other ele- 

 ments required were inorganic, notably sul- 

 fur, phosphorus, and chlorine. 



Chain (19")8) suggested that the position 

 of the oxygen atoms hi the tetracycline 

 molecules on alternate carbon atoms indi- 

 cates some acetate condensation mechanism. 

 Acetate labelled in positions 1 and 2 with 

 radioactive carbon was found to be incor- 

 porated readily into the tctracycliries in 

 positions consistent with this type of mecha- 

 nism of biosynthesis. Chain further believed 

 that the long-chain unsaturated antibiotics 

 of polyene and polyacetylene nature are also 

 built up by acetate condensation. The oc- 

 currence of odd-numbered long fatty acid 

 chains may be due to clecaiboxylation of a 

 dicarboxylic acid. 



Darken et al. (llKiO) ha\-e shown that in 

 the production of tetracyclines the phos- 

 phate-citrate-carbonate ratio is highly criti- 

 cal. As a result of careful study of these in- 

 terrelationships, yields in shaker flasks were 

 raised from an average of loO jug pei" n"il to 

 1350 /xg per ml. The high calcium carbonate- 



citric acid medium permits the calcium ion 

 to act as a seciuestering agent for tetracy- 

 cline, ^'ields were raised in tank fermenta- 

 tions from ^)~) fjLg per ml to 525 ;ug per ml 

 in the high citric acid-ammonia medium, 

 which permits fermentation in the preferred 

 pH range. The seciuestering effect of calcium 

 carbonate becomes apparent as the yields 

 are further raised with this culture to an 

 average of 705 /xg per ml. 



Each molecule of chlortetracycline con- 

 tains one chlorine atom. Antibiotic activity 

 can also be produced in a chloride-deficient 

 medium, or one in which chloride utilization 

 is blocked by the presence of low levels of 

 bromide, leading to the production of a new 

 antil)iotic, tetracycline (Gourevitch et al., 

 1955). Controlled biosynthesis is a deter- 

 mining factor in the ])r()duction of tetracy- 

 cline, chloi-tetracycline, or bromtetracycline, 

 depending on the presence or absence of 

 chlorine or !)romine in a biologically a\'ailable 

 form as a precursor. Tetracycline itself is 

 luiilt up by one-carbon transfers fi'om simple 

 starting materials. So far no carbon com- 

 pound precursors have been found. The 

 biosynthesis of the various chlor- and brom- 

 tet]-acyclines has lieen studied further by 

 Doerschuk r( al. (]!)5(i). 



M isceUaucoK.s A ntihiotic.'^ 



CHLORAMPHENICOL 



This antibiotic is made up of two chemical 

 units, p-nitrophenylserinol antl dichloroace- 

 tic acid. I^y use of a synthetic glycerol 

 lactate medium, it was found that various 

 amino acids and p-nitrophenylserinol stimu- 

 lated chloramphenicol biosynthesis; dichloro- 

 acetic acid did not. Both growing and rest- 

 ing cells of S. venezuelae are capable of 

 acetylation of p-nitrophenylsei'inol to give 

 X-acetyl-p-nitrophenylserinol. Howe\'er, the 

 latter does not act as a precursor of chlor- 

 amphenicol, but being itself an antibiotic, 

 it increases the antibiotic potency of the 

 broth ((iottlieb et at., 1956). 



