p-AMINOBENZOIC ACID 491 



However, it was observed even before the elucidation of the structure of 

 folic acid that concentrations of this vitamin corresponding to those 

 ordinarily required for organisms incapable of folic acid synthesis do 

 not prevent the toxicity of sulfonamide for a number of organisms. 66, 80, 81 

 Even high concentrations of folic acid do not affect the toxicity of sulfon- 

 amides for Escherichia coli 66 and many other organisms. 66, 80, 81, 82 Fur- 

 thermore, mutant strains of Escherichia coli 83 and of Neurospora crassa, 

 which require p-aminobenzoic acid for growth, do not respond to folic 

 acid. For many organisms which require p-aminobenzoic acid, folic 

 acid is either not utilized at any concentration or is utilized less effectively 

 than p-aminobenzoic acid. 66 However, Lampen and Jones 71, 72 have 

 shown that folic acid is more active than p-aminobenzoic acid in support- 

 ing the growth of Streptococcus faecalis (Ralston), and that it prevents 

 noncompetitive^ the toxicity of sulfonamides for this organism as indi- 

 cated in Table 3. The amount of folic acid necessary for reversal of 

 sulfonamides approximates that necessary for growth of the organisms 

 in the absence of sulfonamides. The toxicity of sulfonamides for Strep- 

 tococcus faecalis G1Y2, Streptococcus zymogenes 26 CI, Streptococcus 

 durans S10, or Streptococcus liquefaciens 815 is similarly reversed by low 

 concentrations of folic acid. 71, 72 For a number of organisms, such as 

 Lactobacillus arabinosus and Streptobacterium plantarum, the concentra- 

 tion of folic acid necessary to prevent the toxicity of sulfonamides is 

 considerably higher than the concentration of p-aminobenzoic acid neces- 

 sary to stimulate growth of the organisms. 69 However, approximately the 

 same amount of folic acid is required for reversal of any concentration 

 of sulfonamides. 66, 69 The noncompetitive reversal suggests that folic acid 

 can supply the normal metabolic intermediate involved in the biosyn- 

 thesis of the appropriate coenzyme, but is considerably less effectively 

 utilized than p-aminobenzoic acid. The utilization of folic acid for these 

 organisms cannot be ascribed to its conversion to p-aminobenzoic acid. 

 p-Aminobenzoic acid, however, is converted by Lactobacillus arabinosus 

 to microbiologically active forms of folic acid. 70 The reversal by folic 

 acid of the sulfadiazine inhibition of psittacosis virus (Strain 6 BC) in 

 embryonated eggs (Table 3) is somewhat analogous to the results with 

 Lactobacillus arabinosus and Streptobacterium plantarum. 73, 74 Either 

 p-aminobenzoic acid or folic acid prevents the chemotherapeutic effect of 

 sulfathiazole in mice infected with Toxoplasma (RH strain). 84 



The activity of folic acid under certain conditions in preventing the 

 toxicity of sulfonamides (p. 471) for Escherichia coli indicates that the 

 organism has some slight ability to utilize folic acid in the biosynthesis 

 of the coenzyme involved in production of thymine. However, folic acid 

 cannot substitute for p-aminobenzoic acid in the biosynthesis of meth- 

 ionine, purines and serine in Escherichia coli (p. 470) . 



