CHEMOTHERAPY 



1940, Fildes postulated ihat nmihactcrial substaiucs in q<-ncr;il would 

 be found to interfere with (\ss(MUi;ii (Mizyiiiir re, ui ions of llir f)acterial 

 cell, either by combining with important substrates ("essential metab- 

 olites"), or by competing with them for combination with the enzyme. 

 We shall see in what follows that a number of mechanisms other than 

 "competitive inhibition" can give rise to antibacterial action, but the 

 importance of Fildes' postulation is that it pointed the way clearly for 

 a large amount of experimental work, including the production of 

 many new substances of biological, and probably eventually thera- 

 peutic, activity. In Fildes' illustration — toxicity due to mercuric 

 ions^there was no actual demonstration of the identity or even of the 

 thiol nature of the natural metabolite. But an accompanying paper 

 of Woods contained a classic demonstration of competition between 

 the natural /^-aminobenzoic acid and the artificial drug p-a.m\no- 

 benzenesulfonamide and its derivatives. Since that time, others have 

 furnished many more examples of interference with mammalian as well 

 as bacterial physiological processes, caused by su Instances related 

 chemically to natural metabolites and \'itamins. 



Since much has been written elsewhere and there are discussions 

 in this volume bearing upon competitive inhibition, let us content 

 ourselves with two or three points relating to our chosen theme. First, 

 let us contrast the rationale applied by Ehi'lich and others in synthe- 

 sizing new agents prior to 1940 with a rationale based upon the Fildes- 

 Woods hypothesis. It was customary previously to begin with a toxic 

 principle, e. g., arsenic, mercury, or a dye, and to build up around it 

 various organic structures and substituent groups in the hope of de- 

 veloping a selectivity toward a particular type of cell. The literature 

 of the last few decades is full of reported attempts to "reduce the 

 toxicity" of such agents by appropriate modifications in structure. 

 On the other hand, the warped metabolite molecules now being syn- 

 thesized are likely to contain a special arrangement of relatively 

 common chemical groups, which is at the same time the basis for a 

 rather subtle toxicity and for whatever specificity the substance shows. 

 For example, pantoyltaurine, an inhibitory analogue of pantothenic 

 acid, is an amide derivative formed by joining together two natural 

 products. Other synthetic inhibitors are homologues of natural metab- 

 olites, which presumably combine with the specific enzymes for the 

 very reason that their structure is not exotic. The spectacular recent 



