Antibiotic Research 173 



apparent mass adaptation of large numbers of bacteria 

 to low concentrations in a fluid medium in fact repre- 

 sents the selective multiplication of a few resistant organ- 

 isms, presumably mutants, introduced with the inoculum. 

 Furthermore, repeated attempts to adapt small numbers 

 of bacteria to penicillin by slowly increasing the concen- 

 tration of the antibiotic in the medium over a period of 

 days have in our hands been uniformly unsuccessful. On 

 the other hand, with chloramphenicol, there are some ex- 

 periments which apparently involve no important degree 

 of multiplication or selection and in which an entire bac- 

 terial population has apparently become resistant after 

 exposure to threshold concentrations of the antibiotic for 

 10 to 25 days. Even in these experiments, however, the 

 possibility of a minor degree of multiplication, sufficient 

 to permit spontaneous mutation followed by selective mul- 

 tiplication, has not been rigorously excluded; and there 

 have as yet been no rigorous experiments that prove the 

 adaptation of bacteria to antibiotics. 



As to the mechanisms that determine the varying re- 

 sistance of bacterial species and strains to antibiotics, at 

 least four have now been demonstrated for penicillin 

 alone, and there may well be more. Some bacteria are re- 

 sistant because they are able to release into the medium an 

 enzyme, penicillinase, which converts penicillin to an in- 

 active form, penicilloic acid. Others that do not release 

 penicillinase into the medium are able rapidly to destroy 

 the antibiotic after it gets into the cell. For most bacteria 

 as they occur in nature, however, the primary determinant 

 of penicillin sensitivity appears to be the affinity of cer- 

 tain penicillin-vulnerable components of the cell and the 

 antibiotic. By using radioactive penicillin it has been 

 possible to show that penicillin-sensitive bacteria have a 

 high combining affinity for the antibiotic, and that rela- 

 tively penicillin-resistant organisms have a correspond- 

 ingly lower reactivity. We are not dealing here with a 



