ALTERNATIVE HYPOTHESES OF SULPHONAMIDE ACTION 165 



and like substances for an essential enzj-me system, and that the amino-acid concentrates 

 are effective because they are substrates or products of the essential enzyme, which to 

 some extent can be replaced by artificial hydrogen carriers. 



Other Sulphonamide Antagonists. 



There is a large group of substances capable of antagonizing sulphonamides. 

 For example, antagonizers are found in necrotic tissue and abscesses (Lockwood 

 et al. 1938), in pus (MacLeod 1940), and, as we have already noted, in the com- 

 plex organic ingredients of routine culture media (see Strauss and Finland 1941). 

 In some of these the active principle may be ^^-aminobenzoic acid, though it is 

 unproven. Among other substances structurally unrelated to j9-aminobenzoic 

 acid that are reported as antagonists are methionine (Kohn and Harris 1941), 

 co-enzyme I (West and Coburn 1940), nicotinic acid and nicotinamide (Dorfman 

 et al. 1940), urethane (Johnson 1942), purine bases (Martin and Fisher 1942, Snell 

 and Mitchell 1942) and certain amino-acids. 



Kohn and Harris postulated that a methionine phase of metabolism was secondary 

 to a phase for which p-aminobenzoic acid was a catalyst, and that when the latter was 

 blocked by sulphanilamide, added methionine enabled the essential metabolism to carry 

 on. With regard to co-enzyme I and nicotinamide, Strauss, Dingle and Finland (1941) 

 could not confirm West and Coburn's observation that co-enz_vme I antagonized the 

 inhibition of staphylococci by sulphapyridine, but found a partial antagonism of sulpha- 

 guanidine by a combination of uracil, pyruvate and adenyhc acid. Koser and his colleagues 

 (Dorfman and Koser 1942, Berkman and Koser 1943) have defined some of the conditions 

 in which co-enzyme I and nicotinamide are active. Using a strain of Sh. sonnei in a basal 

 medium they found that these substances antagonized the inhibition of its respiratory 

 activity by sulphapjTidine and sulphathiazole, but not inhibition by sulphanilamide, 

 sulphadiazine, sulphaguanidine or sulpliacetamide. Para-aminobenzoic acid was antago- 

 nistic to all the sulphonamides tested, though its effect on sulphapyridine and sulpha- 

 thiazole was less than that of nicotinamide. They concluded that the radicle attached 

 to the sulphonamide part of the molecule could also affect the enzyme sj'stems of the 

 cell, and that in this case the structural similarity of the pyridine or thiazole rings in 

 sulphapyridine and sulphathiazole with nicotinic acid was responsible for inhibition of 

 respiratory activity dependent upon nicotinamide (pyridine-carboxamide) and co-enzyme I 

 (diphospho-pyridine nucleotide) (see also v. Euler 1943, Teply et al. 1943). Antagonism 

 by amino-acids is illustrated by a recent report of Sevag and Green (1944) who reversed 

 the sulphonamide inhibition of Staph, aureus in a medium containing glucose and certain 

 amino-acids by the addition of tryptophan. 



Alternative Hypotheses of Sulphonamide Action. 



The success of the Woods-Fildes hypothesis in predicting the inhibitory activity 

 of analogues of growth factors does not necessarily confirm the truth of the hypo- 

 thesis in relation to sulphonamide-action, though it provides a strong incentive 

 to give the hypothesis priority of place. The student is referred to the review 

 of Henry (194.3) for a full discussion of the objections to the hypothesis. We 

 shall do no more than summarize the main points. 



Neither the competitive relationship between sulphonamides and ;p-amino- 

 benzoic acid, nor their structural similarity, necessarily signifies a competition 

 for an enzyme system utilizing j9-aminobenzoic acid. In the first place j9-amino- 

 benzoic acid antagonizes sulphonamide inhibition of systems in which it can play 

 no essential part ; e.g. the carboxylase system of Staph, aureus (Sevag et al. 1943), 

 the digestion of starch by diastase, and the adsorption of methylene blue to charcoal 

 (Eyster 1943). Moreover, the rates of inhibition and antagonization may differ 



