GENETIC AND METABOLIC MECHANISMS 



UNDERLYING MULTIPLE LEVELS OF 



SULPHONAMIDE RESISTANCE IN PNEUMOCOCCI 



ROLLIN D. HOTCHKISS AND AuDREY H. EvANS 



The Rockefeller Institute, New York 



Development by bacteria of resistance toward a drug to 

 which they are normally sensitive not only challenges the 

 medical men, sworn enemies of bacteria, but has lately com- 

 manded the attention of those whose interest in bacteria is 

 that of admirers, the biochemists, as well as those historians, 

 the geneticists. Demonstration by Demerec (1945) that drug 

 resistance in bacteria could be the result of discrete muta- 

 tional events, led us to seek stable sulphanilamide resistance 

 in Pneumococcus which might be transferred to sensitive 

 cells by the technique of transformation. Heritable transfer 

 of specific capsule synthesis had been discovered by Griffith 

 (1928) as an in vivo transformation. Langvad-Nielsen (1944) 

 could not demonstrate transformation of pneumococci to 

 sulphonamide resistance, but one must recall that in using 

 the Griffith procedure, he was requiring transfer of both drug 

 resistance and encapsulation (or resistance and mouse 

 virulence) at once, an event we now have reason to consider 

 unlikely. Even after the classic discovery of Avery, MacLeod 

 and McCarty (1944) that the capsule -transforming activity 

 was associated with cell deoxyribonucleate (DNA), our first 

 attempts in 1948 to induce sulphonamide resistance failed for 

 various reasons. It was penicillin resistance and strepto- 

 mycin resistance which were the object of the first quanti- 

 tative transformations (Hotchkiss, 1951), and since that time 

 this type of marker has been much used. Sulphonamide 

 resistance transformations were successfully achieved by the 

 present authors in 1952, but although mentioned a number 



183 



