BIOCHEMICAL ANTAGONISM 



facts, it is reasonable to assume that the sulfonamides produce a 

 crippling deficiency of /)-aminobenzoic acid in the organisms. This 

 view is strengthened when one recalls that structural analogues of 

 certain other vitamins and hormones call forth in animals certain 

 signs associated with specific deficiency diseases. It cannot be said 

 that such antagonisms in any way lend proof to the hypotheses which 

 have been advanced to explain the action. Nevertheless, it is not 

 advisable to allow arguments about mechanism to obscure the well- 

 established facts in the case. 



Finally, to end our consideration of the first aspect, let us note 

 examples of some biochemical reactions which have been uncovered 

 by means of microorganisms rendered resistant to the action of an 

 inhibitory analogue. By long-continued culture of a bacterial or 

 fungal species in the presence of gradually increasing concentrations of 

 an inhibitor it is possible to derive a strain which is resistant, or fast, 

 to the agent. By use of a strain of Endomyces vernalis made fast to 

 pyrithiamin, it was possible to show that the acquired resistance was 

 correlated with the appearance of a system which cleaved the inhibitor 

 into its component pyrimidine and pyridine portions. This demon- 

 stration prompted examination of naturally resistant species, that is, 

 those which synthesized thiamin. These forms were found to possess 

 the pyrithiamin-destroying system. Without the use of the "fast" 

 variant, the recognition of this biochemical reaction would have been 

 more difficult. 



The second new aspect to open before us is the possibility of 

 producing new types of drugs by application of the knowledge that 

 pharmacological signs of a predictable nature may be produced by 

 metabolite analogues. The cataloguing of the various specific histo- 

 logical and biochemical manifestations of deficiency of each of the 

 vitamins and hormones is progressing rapidly. It may be desirable 

 to evoke one or more of these signs. If this should be so, then the 

 synthesis and trial of an inhibitory analogue of the metabolite in 

 question would be indicated. Already it has been seen that pharmaco- 

 logical manifestations predictable at least in part can be called forth 

 by the proper metabolite analogue. In this connection, a retrospec- 

 tive glance at the case of 3,3'-methylenebis-[4-hydroxycoumarin], 

 may be profitable. This agent produces signs similar to those seen 

 in vitamin K deficiency, and these manifestations form the basis of 



