172 Bernard D. Davis 



concatenation of facts appeared to exclude all but one of the 

 seven mechanisms listed above. The conclusion, reached thus 

 by exclusion, was that the mutants were resistant by virtue of 

 producing an enzyme with decreased affinity for the inhibitor 

 relative to the competitive metabolite. 



The ratiocination involved in this study provided the author 

 with a good deal of entertainment, much like that involved in 

 trying to solve a detective story before the last chapter. But 

 as with such a story, one cannot be sure of the relevance of 

 the conclusion to real life. It would be highly desirable to 

 demonstrate directly, with extracted enzymes, the inferred 

 change in affinity. Unfortunately, though the PAB/sulphon- 

 amide interaction is the prototype of competitive inhibition, 

 it has been studied only with intact cells; the biosynthetic 

 reaction of which PAB is substrate is still unknown. The 

 same is true of POB. And while growth-inhibiting analogues 

 are known for a variety of other metabolites, including amino 

 acids and vitamins, the biosynthetic reactions in which these 

 metabolites participate are also by and large not enzymically 

 defined. 



Alterations in an extracted enzyme, nitro reductase, have 

 been reported in bacteria resistant to chlortetracycline 

 (aureomycin) (Saz, Brownell and Slie, 1956). It is not certain, 

 however, that inhibition of this enzyme is the basis of action 

 of the drug. 



Specific permeation systems 



Shortly after EhrHch developed the effective chemotherapy 

 of trypanosomiasis with arsenicals he encountered the 

 phenomenon of drug resistance. Furthermore, he showed 

 that resistant strains took up less of the drug than sensitive 

 ones, and concluded that resistance might be based on 

 decreased permeability to the drug or on a decreased number 

 of receptors that can bind the drug. However, whether one 

 is measuring arsenic or modern radioactive antibiotics, a 

 decreased uptake of drug by resistant cells does not alone 

 distinguish these two mechanisms. Furthermore, our thinking 



