164 ANTIBACTERIAL SUBSTANCES FOR TREATMENT OF INFECTIONS 



and pantoyltaurine, in which the — COOH group is replaced by — SO3H, were found to 

 be similarly related (see also Barnett and Robinson 1942). Recently Mcllwain (1943a) 

 has further elucidated the action of pantoyltaurine by comparing the metaboUsm of 

 resistant and susceptible strains of C. diphtherice and Str. -pyogenes. Pantothenic acid 

 is an essential nutrient for susceptible strains of both species. Resistance could be induced 

 in C. diphtherice by serial subculture either in media containing sub -inhibiting amounts 

 of pantoyltaurine, or in media lacking pantothenate ; and aU resistant strains were shown to 

 have developed the power to use /S-alanine, which they presumably synthesized into 

 pantothenic acid. Resistant Str. pyogenes had developed no ability to synthesize panto- 

 thenate. They were, however, susceptible to salicylate and pantoyltaurine, suggesting 

 that resistance to pantoyltaurine alone is due to the possession of an alternative metabolic 

 process, which in turn is susceptible to sahcylate (see also Ivanovics 1942). Mcllwain 

 and Hughes (1944) have also shown that pantothenate is metaboUzed by Str. pyogenes 

 during glycolysis, but that neither absence of pantothenate nor its antagonization by 

 pantoyltaurine affects the glycolysis. On the other hand, either the absence of panto- 

 thenate, or the addition of pantoyltaurine, or the inhibition of glycolysis, will inhibit 

 growth. These facts are most conveniently explained by assuming that both glycolysis 

 and pantothenate are necessary for the formation of an essential growth-metaboUte in 

 the cell. 



Pantoyltaurine is of particular interest since Mcllwain (194:2a) was able to 

 collect data from which he predicted its in vivo action. The antibacterial index 

 for Str. pyogenes was as low as 500 ; the molar concentration of pantothenic acid 

 likely to be found in animal tissues lay between 10^^ and 10~^; and the molar 

 concentration of pantoyltaurine required to inhibit the streptococci in the presence 

 of this amount of pantothenic acid was well below the maximum tolerated con- 

 centration. The prediction that pantoyltaurine would be chemotherapeutic in vivo 

 was amply confirmed by Mcllwain and Hawking (1943). Rats were protected 

 against 10,000 lethal doses of Str. pyogenes, and the protective effect was abolished 

 by artificially raising the pantothenate concentration of the blood. The drug 

 was ineffective in mice, in whose tissues the natural pantothenate content is 

 higher. 



WooUey and White (1943) have also demonstrated a resistance to an antibacterial 

 substance of the Woods-FUdes type, which, like that of Str. pyogenes to pantoyltaurine, 

 does not depend on an abUity to synthesize increased amounts of the essential metabolite. 

 Pyrithiamine, the pyridine analogue of thiamin, inhibited the growth of yeast and bacteria 

 in direct proportion to their natural thiamin requirements. But the resistant strains 

 produced neither thiamin nor any other pyrithiamine antagonist in detectable amounts. 

 Failure to demonstrate increased synthesis of the essential metabolite by drug-resistant 

 organisms does not, however, invahdate the Woods-Fildes hypothesis. The resistant 

 organism may develop a different unrelated path along which to carry its essential metabohc 

 processes. 



Further examples of antagonism are described in connection with other antibacterial 

 agents. We may note here, for example, that polyamines like triethylenetetramiae 

 and tetraethylenepentamine antagonize the bacteriostatic effect of mepacrine on Bact. coli 

 (Silverman and Evans 1943) and of propamidine on L. casei and Str. lactis (SneU 1944). 

 Mcllwain (19416) has apphed the Woods-FUdes hypothesis to the antagonism of nucleic 

 acid and related substances to acrifiavine. As in the sulphonamides, there was a constant 

 ratio between inhibitor and antagonist. Amino-acid concentrates, especially in the 

 presence of artificial hydrogen carriers like methylene blue, were also antagonistic, but 

 with increasing concentrations of inhibitor, increasing concentrations of antagonists 

 became ineflfective. Mcllwain concludes that the acrifiavine competes with nucleic acid 



