SULPHONAMIDE ANTAGONISTS 161 



and Selbie 1943&). The degree of resistance acquired appears to depend mainly 

 upon the strain, but partly upon the culture medium in which the training takes 

 place. The concentration of drug required to induce resistance is proportional 

 to the bacteriostatic potency of the drug used, and the resistance, once acquired, 

 is sufficiently estabUshed as a character of the strain to withstand serial subculture 

 in media free from the sulphonamide. 



Resistance can also be induced in vivo (MacLean et al. 1939, Schmidt and 

 Hilles 1940, Frisch and Price 1941, Vivino and Spink 1942). For example, Schmidt, 

 Sesler and Dettweiler (1942) infected sulphapyridine-treated mice with virulent 

 pneumococci, pooled the cultures from the heart blood of the mice which died, 

 and with the pooled cultures infected another group of sulphapyridine-treated 

 mice. Two to three repetitions of this process caused an appreciable increase 

 of in vitro resistance, and three to nine repetitions produced a maximal degree 

 of resistance. The acquired resistance was sufficiently established to withstand 

 215 passages through normal mice. The eff"ect of the drug does not appear to be 

 one of selective breeding out of naturally resistant variants, but a direct action 

 on all the metabolizing cells in the culture. 



The practical implication of in vivo induction of resistance, namely the possi- 

 bility that inadequate doses of sulphonamide given to an infected animal might 

 enable the infecting organism to develop a resistance even to adequate therapy 

 by the same drug, is discussed more fully in Part IV. 



The nature of the resistance is not clear. It appears to be specific for the 

 sulphonamides, because an increase in resistance to one member of the series is 

 accompanied by an increase in resistance to the other members. This sulphon- 

 amide cross-resistance is not quantitatively complete, for high concentrations of 

 the more potent sulphonamides will inhibit bacteria that are fully resistant to 

 less potent sulphonamides (see Kirby and Rantz 1943). Nevertheless, its quali- 

 tative specificity is sufficiently striking to suggest that in all cases the acquisition 

 of resistance depends on a metabolic response to a common feature of the sulphona- 

 mides, namely the joara-aminobenzene part of the molecule. Suli^honamide- 

 resistance is not associated with resistance to antibacterial agents such as pro- 

 pamidine, the acridines (Mcintosh and Selbie 19436), penicillin (Powell and 

 Jamieson 19426, McKee and Rake 1942, McKee, Hamre and Rake 1943, 

 Tillett et al. 1943, Schmidt and Sesler 1943), and certain sulphones (Evans et al. 

 1944). 



Sulphonamide Antagonists. para-Aminobenzoic Acid. 



Stamp (1939) was the first to demonstrate sulphonamide antagonizers in 

 bacteria. From broth cultures of a Group A and a Group C streptococcus he 

 isolated a fraction antagonizing both sulphanilamide and sulphapyridine. The 

 substance was heat-stable, of low molecular weight, and appeared to contain 

 amino-acids ; its action was specific for the sulphonamides, but independent of 

 the nature of the organisms inhibited by the sulphonamide. Stamp suggested 

 that the antagonizer was either a metabolite or part of an enzyme system essential 

 for the growth of the organism. Green (1940) found a similar antagonist in Br. 

 abortus, and in various animal and vegetable materials, and postulated that resist- 

 ance of bacteria in presence of sulphonamide depended on their capacity for an 

 initial proliferation rapid enough to produce a high intracellular concentration 

 of antagonizer (see also Pike and Foster 1944). 



The indications that an antagonizing fraction isolated from yeast contained 



P.B. G 



