XIII. SULFONAMIDE REVERSAL 71 



synthesis is inhibited by sulfonamides, these studies were not in thorn- 

 selves instrumental in describing; the derivative. 



The site of action of the sulfonamides has ))een ehicidatcd from several 

 other lines of investigation that appeared at the time to be unrelated. 



When certain sulfonamides are incorjiorated into /»>//«/// 'purified diets 

 adeciuate with respect to thiamine, riboflavin, j)yridoxine, nicotinic acid, 

 and i)ant()thenic acid, typical signs of dietary deficiency are produced in 

 rats consuming such diets.'^"^* Nielsen and Elvehjem''* were the first to 

 report that the deficiency thus induced could be alleviated with folic acid 

 concentrates and biotin. The effectiveness of folic acid was soon confirmed 

 in a number of laboratories.''^"*^ These animal studies were the first to show 

 that folic acid could be a derivative of PABA whose synthesis, in this case 

 by intestmal bacteria, is inhibited by sulfonamides. 



A remarkably specific effect of sulfonamides in inhibiting folic acid 

 synthesis in vitro was pointed out by Miller*^ in tests with Escherichia coli. 

 In her studies folic acid synthesis was 5 to 10 % of that observed in controls, 

 while synthesis of other B vitamins was not significantly altered. 



Further evidence that the primary mode of action of the sulfonamides is 

 in inhibiting synthesis of folic acid from PABA is contained in experiments 

 of Lampen and Jones-^' -^ with folic acid-dependent and -independent 

 strains of lactobacilli. These investigators observed that lactobacilli with a 

 growth factor requirement for folic acid are relatively non-susceptible to 

 inhibition by sulfonamides, whereas those strains that can make their own 

 folic acid are readily inhibited. 



The structure of evidence that sulfonamides act primarily by inhibiting 

 the synthesis of folic acid from PABA was essentially complete when it 

 was finally announced by Angier et al}^ that foHc acid is a derivative of 

 PABA. 



" S. Black, J. M. McKibbin, and C. A. Elvehjem, Proc. Soc. Exptl. Biol. Med. 47, 



308 (1941). 

 " J. B. IMacKenzie, C. G. MacKenzie, and E. V. McCollum, Science 94, 518 (1941). 

 ^' F. S. Daft, L. L. Ashburn, and W. H. Sebrell, Science 96, 321 (1942). 

 « F. S. Daft, L. L. Ashburn, S. S. Spicer, and W. H. Sebrell, U. S. Public Health 



Repts. 57, 217 (1942). 

 " A. D. Welch, Federation Proc. 1, 171 (1942). 

 ** E. Nielsen and C. A. Elvehjem, /. Biol. Chem. 145, 713 (1942). 

 " A. D. Welch and L. D. Wright, J. Nutrition 25, 555 (1943). 

 « F. S. Daft and W. H. Sebrell, U. S. Public Health Rcpts. 58, 1542 (1943). 

 '' G. J. Martin, Proc. Soc. Exptl. Biol. Med. 51, 353 (1942). 

 ^s A. Romberg, F. S. Daft, and W. H. Sebrell, Proc. Soc. Exptl. Biol. Med. 58, 46 



(1945). 

 " A. K. Miller, Proc. Soc. Exptl. Biol. Med. 57, 151 (1944). 

 50 R. B. Angier, J. H. Boothe, B. L. Hutchings, J. H. Mowat, J. Semb, K. L. H. 



Stokstad, Y. SubbaRow, C. W. Waller, D. B. Cosulich, M. J. Fahrenbach, M. K. 



