176 ' Bernard D. Davis 



And now, what can we say about the relation of this work 

 to drug resistance? 



It is clear that a variety of specific permeation systems 

 exist in bacteria ; only a few have been sought, and they have 

 been readily found. It therefore seems unlikely that non- 

 specific pores in the membrane are important in bacteria 

 except for perhaps the smallest molecules and possibly 

 lipophilic substances. Furthermore, permeation systems, like 

 enzymes, can be gained or lost by mutation, as has been shown 

 for all the systems noted above. Finally, the number of 

 permeation units per cell varies under different conditions, as 

 could be shown by measuring the ratio of internal to external 

 TMG. Applying these facts to the problem of drug resistance, 

 it is easy to imagine that mutations, as well as physiological 

 adaptations, could alter the number of units for transporting a 

 drug, and hence could establish various characteristic ratios 

 of internal to external free drug. Thus, though the passive 

 model of cell permeability was quite unsatisfactory as a basis 

 for explaining various degrees of drug resistance, "perme- 

 ability" in the active sense described here makes possible a 

 theoretically satisfactory solution. However, these concepts 

 are so new that they have only begun to be applied to the 

 problem of drug resistance. For example, it has been shown 

 that some penicillin-resistant bacteria take up less of the 

 inhibitor than sensitive strains while others do not. Perhaps 

 Dr. Eagle, who has done much of this work, will discuss it 

 here. 



Some work of my colleagues (Maas and Frosch, unpublished) 

 provides rather direct evidence for decreased permeability as a 

 mechanism of resistance to the inhibitory action of D-serine 

 on Esch. coli. This inhibitor has the advantage that its mode 

 of action has been established as competitive inhibition of a 

 biosynthetic enzyme, pantothenate synthase, whose activity 

 can readily be measured in intact cells and in extracts (Maas 

 and Frosch, unpublished; Maas and Davis, 1950). 



The effect of D-serine is shown in Table I, in which wild- 

 type Esch. coli is compared with a D-serine-resistant mutant 



