STRUCTURAL ANALOGUES 145 



It cannot be that sulphonaniide exerts its effect by preventing the synthesis of 

 p-aminobenzoic acid since the antagonism is a competitive one and occurs when the 

 p-aminobenzoate is already present. Hence the interference is with the utiUsation of 

 the metaboUte, and at least part of the effect is probably due to interference with the 

 synthesis of folic acid. It will readily be appreciated that the enzyme system respon- 

 sible for fohc acid synthesis will have an affinity for the structural groups of p-amino- 

 benzoic acid and for the closely similar sulphonamide molecule. There is little doubt 

 that in many enzyme reactions combination between the enzyme and substrate must 

 occur before activation of the substrate occurs. 



Like so many biological phenomena the relation of p-aminobenzoic acid to the 

 bactericidal effect of sulphonamide is not a simple one. It appears that other meta- 

 bolites like the amino acid methionine, and the purines apparently unrelated to 

 p-aminobenzoate, also function as sulphonamide antagonists ; but this may be due 

 to the fact that p-aminobenzoate (or folic acid) is a coenzyme in the synthesis of 

 methionine, etc., and when these metabolites are supplied ready-made the coenzyme 

 and synthetic mechanism are not required anyway, so that sulphonamide inhibition 

 of the system is ineffective as far as bacterial growth is concerned. Other evidence 

 also suggests that p-aminobenzoate may have other functions in metabolism besides 

 being an intermediate in the synthesis of folic acid. 



It is interesting to note that sulphanilamide affects plant growth by stopping 

 nuclei coming into pro-phase so that cell division is reduced, and by an effect on the 

 spindle mechanism, anaphase movement is inhibited. As with bacteria, so with 

 plants, the effect of sulphanilamide is reversed by p-aminobenzoic acid (Hindmarsh, 

 1949). 



A number of other cases of bacterial inhibition by sulphur analogues of growth 

 substances and intermediate metabohc products have been studied. Pyridine-3- 

 sulphonic acid inhibits the bacterial growth promoting activity of pyridine-3-carboxy- 

 lic acid (nicotinic acid). The sulphonic acid analogue pantoyltaurine (CsHjgOgN.SOgH) 

 inhibits bacterial growth, and the inhibition is antagonised by the carboxylic acid 

 analogue pantothenic acid (CgHigOsN.COOH). 



It is not only sulphur analogues that inhibit the gro^vth of bacteria (and other 

 cells) by selective combination with enzyme in place of the natural substances. 

 Dichloroflavin (R.Clg) inhibits the growth of organisms requiring riboflavin 

 (R. (0113)2), and interference with the utilisation of riboflavin was also produced by 

 dihydroriboflavin, lumichrome. 



Harington (1948) has effected the synthesis of the sulphur analogue of 

 thyroxine. 



I I 



ho/ y^"^ >CH2.CHNH2.COOH 



I I 



Th yroxin e 



H2.CHNH2.COOH 



Sul phur analo gue 



