XIII. SULFONAMIDE REVERSAL 67 



Woods and Fildes,'' and subsequently Woods^ in more detail, showed that 

 the sulfonamide-reversing agent present in yeast in addition to being sta])le 

 to heat, acid, and alkali, as reported liy Stamp, is inactivated by nitrous 

 acid, acetylation, or esterification. These data together with a considera- 

 tion of the solubility and acid-dissociation constant of the sulfonamide- 

 reversing agent led to a trial of synthetic PABA. This compound proved 

 highly active as a sulfonamide-neutralizing compound not only in vitro 

 but also in vivo against sulfanilamide in the treatment of a hemolytic 

 streptococcal infection of mice.^ Although the sulfonamide-neutralizing 

 activity of natural material was not isolated and identified as PABA by 

 Woods, this was accomplished subsequently by Rubbo and Gillespie^ 

 and by Bianchard.^ 



Woods' observation* that PABA is highly active in reversing the bac- 

 teriostatic action of the sulfonamides has been confirmed in many labora- 

 tories and against many strains of bacteria. PABA does not, however, 

 reverse sulfonamide action in all species. Bacterium tularensis being the 

 best-known exception.^ 



Since PABA is an effective reversing agent for the sulfonamides, at least 

 in the case of the majority of microorganisms, it was apparent to Woods 

 that the development of sulfonamide resistance in bacteria may be as- 

 sociated with increased synthesis of PABA.* For a critical test of this hy- 

 pothesis, a specific test for PABA was essential. With the development by 

 Landy and Dicken'" of a microbiological assay for PABA based on the 

 essential nature of this compound for Acetohacter suhoxydans, the synthesis 

 of PABA by sulfonamide-sensitive and sulfonamide-resistant bacteria 

 could be examined. Landy and co-workers^^ observed in culture filtrates 

 from sulfonamide-resistant staphylococci fifty to one hundred times as 

 much PABA as was encountered in culture filtrates from sulfonamide- 

 sensitive strains. Increased PABA synthesis occurs even when the strains 

 of staphylococci are grown for many generations in the absence of sulfon- 

 amides. Similar findings with respect to the synthesis of large amounts of 

 PABA by sulfonamide-resistant staphylococci were recorded by Spink 

 et al.,^^ using both the Acetohacter suhoxydans^^ and the Lactobacillus arahino- 



^D. D. Woods and P. Fildes, J. Soc. Chem. Ind. {Loudon) 59, 13.3 (1940). 

 5 D. D. Woods, Brit. J. Exptl. Pathol. 21, 74 (1940). 

 « F. R. Selhic, Brit. J. Exptl. Pathol. 21, 00 (1940). 

 ' S. D. Rul)l)o and J. M. Gillospie, Nature 146, S.38 (1940). 

 » K. C. Blanchard, ./. Biol. Chem. 140, 919 (1941). 

 9 J. T. Tamura, ./. Bacterial. 47, 529 (1944). 

 '» M. Landy and D. M. Dickon. /. Biol. Chem. 146, 109 (1942). 



" M. Landy, N. W. Larkum, K. J. Oswald, and F. St leiglitofT, Hciencc 97, 265 (1943). 

 '2 W. W. Spink, L. 1). Wright, J. J. Vivino, and H. R. Skeggs, ./. Exptl. Med. 79, 331 

 (1944). 



