SULPHONAMIDE RESISTANCE IN PnEUMOCOCCI 187 



Nature of Sulphonamide Resistance 



The possibility of defining the physiological mechanism 

 which implements such a subtle series of genetic controls, 

 has led us to study the effect of sulphonamides upon these 

 mutants and transformants. It is possible to infer from the 

 literature that the drug acts upon a system utilizing p-amino- 

 benzoate (PAB) and leading to the production, first of com- 

 pounds related to folic acid, and through them, of cell sub- 

 stance (Fig. 1). In support of this inference, it can be shown 



Competition between 

 p -amino -ben zoic and sulfonamide drugs 



NHg/ \c00H JiH/^ \5O2NHR 



^^ ^ ^^ 



Unknown 

 enxyme system 



I 



TOLIC ACID 



coenzyme 

 form I 



1- carbon 

 intermediates 



^glycine *- serine 



+ homocysteine >- methionine 



+ precursors »- thymine 



+ imidazol deriv. >- purines 



Fig. 1. 



— *' proteins 



nucleic 

 acids 



that these sensitive and resistant strains of Pneumococcus 

 all withstand more sulphanilamide (SA) in the presence of 

 added PAB. The drug and metabolite compete in the classical 

 way defined by Woods (see e.g. Woods, 1950), and SA/PAB 

 molar ratios giving partial growth inhibitions are essentially 

 constant over 50-fold ranges of absolute concentration. The 

 retention of resistance over wide ranges of absolute concen- 

 tration serves to eliminate hypotheses based upon possible 

 changes in the rates of supply or utilization of metabolite or 

 drug. 



