Drug Resistance in Bacteria 11 



such cases the further assumption is sometimes made that an 

 initial proUferation of the inoculated cells occurs through the 

 intervention of impurities in the plate-medium, and that 

 during the process mutations occur so that each of the micro- 

 colonies formed in this preliminary growth contains at least 

 one mutant. This mutant can then eventually multiply to 

 give the final colony. Objections to the universal application 

 of the underlying assumptions have already been mentioned. 

 However, when they are accepted they are usually coupled 

 w^ith the analogous one that if a large enough inoculum is 

 plated those few cells which form colonies not later than a 

 given relatively short time, regarded as the normal develop- 

 ment time, represent the mutants initially present. 



To test the likelihood of this interpretation experiments 

 have been made on the rate of development of colonies of 

 Bad. coli rnutabile on lactose-agar and of Bad. ladis aerogenes 

 on D-arabinose-agar. Inocula were varied from 10 to 10^, and 

 distributions of sizes and numbers of colonies at various times 

 were recorded (Dean and Hinshelwood, 1956; McCarthy and 

 Hinshelwood, 1957). 



The conclusion reached was that in these examples the 

 colonies which appeared the earliest need not be ascribed to 

 any special mutant type but represented nothing more than 

 the tail of the nearly Gaussian distribution which the develop- 

 ment times (for a given colony size), or the sizes at a given 

 time, were found to follow. 



Time -Number Relations 



When resistance can be developed by training, the assump- 

 tion commonly made is that drug-resistant mutants are 

 present in minute proportion in the culture before it has ever 

 been exposed to the drug. Some cultures may, of course, be 

 heterogeneous, containing cells with a higher natural resist- 

 ance than others, and such cells would be enriched by selection. 

 This, however, is quite a different proposition from the denial 

 of direct adaptive processes as possible in themselves. 



