COMPETITIVE ANALOGUE-METABOLITE INHIBITION 477 



Many organisms resistant to an inhibitory analogue do produce in- 

 creased amounts of the metabolite. This can be demonstrated by assay of 

 the cultures for the metabolite. Although in such a case considerably 

 more of the analogue is required for inhibition of growth in the absence 

 of an exogenous supply of the metabolite, the inhibition index appearing 

 with increased supplemental concentrations of the metabolite does not 

 differ from that of the normal strain. 



For resistant strains of organisms showing increased inhibition indices, 

 classification in the above groups is difficult, since resistant organisms of 

 all the types 2-5 would be expected to have increased inhibition indices. 

 If the resistant organisms of type 4 are able to dispense completely with 

 the normal route of biosynthesis, such organisms would be expected to be 

 completely resistant to the analogue. 



Destruction of the inhibitor by the organism is known to account for 

 the resistance in some strains which tolerate larger amounts of the in- 

 hibitor. If the rate of destruction of an inhibitory analogue is not too 

 rapid, the inhibition index determined at high concentrations of metab- 

 olite and inhibitor would not be expected to be appreciably altered. 



Specific phases of acquired resistance to the inhibitory action of ana- 

 logues are discussed in subsequent sections. 



Competitive Metabolite Antagonists and Biochemical Genetics 



When Escherichia coli is sub-cultured in an inorganic salts-glucose 

 medium containing sulfanilamide and methionine as well as glycine, 

 serine and xanthine, a strain develops which requires methionine for 

 growth 58 and cannot utilize homocystine. 59 The mutant strain does not 

 develop in the absence of either sulfanilamide or methionine. Though 

 evidence has been presented which indicates that the mutant strains of 

 this type have a greater growth rate than the parent strain, 00 the mech- 

 anism by which the mutant strain is obtained appears to be more com- 

 plex than that of spontaneous mutation and selection. This mutant strain 

 is particularly interesting, since sulfanilamide prevents the biosynthesis 

 of methionine at the stage corresponding to the deficiency of the mutant 

 strain. 59 Similarly, a strain of Escherichia coli requiring both methionine 

 and purines has been obtained from serial sub-cultures in the presence 

 of sulfanilamide in a medium containing both methionine and purines. 61 

 The purine requirements of the mutant strain are analogous to the re- 

 quirements of the parent strain cultured in the presence of sulfonamides. 01 

 From these results, it appears possible that competitive inhibitors of 

 metabolites may play a role in the elucidation of the biochemical rela- 

 tionship of enzyme to gene. 



From crosses of a sulfanilamide-resistant strain to wild type, a strain 

 of Neurospora which appeared to require sulfanilamide for growth was 



