Modern advances in therapeutics : presidential address / by Sir Edward Mellanby.

  • Edward Mellanby
Date:
[1951?]
Catalogue details

Licence: In copyright

Credit: Modern advances in therapeutics : presidential address / by Sir Edward Mellanby. Source: Wellcome Collection.

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    has proved effective in Babesia infections in dogs and in cattle. Another biochemical hypothesis, which played its part in building up the modern conception of chemotherapeutic action, was that of Voegtlin, who regarded the action of arsenoxide produced in the body from arsphenamine and other curative arsenic derivatives as due to the arsenoxide radical combining with the thio radicals of gluta¬ thione in the cell protoplasm and thereby interfering with its respiratory mechanism. At a later stage, Fildes explained the disin¬ fectant action of mercury salts on a similar basis, suggesting that the mercury ions com¬ bined with and inactivated the free thiol groups in bacteria and so suppressed their respiration. With the development of the sulphon- amides Fildes further advanced the hypo¬ thesis of a biochemical basis for chemo¬ therapeutic action and assumed that these agents acted on some chemical mechanism necessary for the growth of the cell and so put out of action an ‘essential metabolite’ or a growth factor or an enzymic system. This hypothesis received support from the work of Stamp who found that a sterile extract of streptococci added to the culture medium, antagonised and neutralized the bacteriostatic effect of sulphanilamide on living bacteria. Finally, Woods, in Fildes’s laboratory, found that an extract of yeast also antagonized the action of sulphanilamide and he pro¬ ceeded to bring evidence to show that the cell constituent which had this action was probably p-aminobenzoic acid. p-ami nobenzoic acid So2nh. 2 1 & Sulphanilamide It will be seen that the structural formulae of p-aminobenzoic acid and sulphanilamide are closely similar. Woods suggested that sulphanilamide occupied the enzymic system normally taken by p-aminobenzoic acid and thereby deprived the cells of this essential metabolite. In support of his hypothesis, Woods found a fairly constant proportion between the concentration of sulphanilamide in a medium and the concentration of p-ami- nobenzoic acid necessary to neutralize its bacteriostatic effects: he also found that the concentration of p-aminobenzoic acid re¬ quired to abolish the effects of different suiphonamide derivatives increased with their bacteriostatic activity. I shall not dis¬ cuss further this subject of biochemical analogues, which has opened up many new fields of enquiry. I realize there are still difficulties to be overcome before the rela¬ tion of p-aminobenzoic acid to sulphanil¬ amide action can be fully accepted, not the least being the present inability to detect p-aminobenzoic acid itself in pathogens. There is, however, no longer any doubt that the main hypothesis of the antagonism of many biochemical analogues is a conception of fundamental importance in the bio¬ chemistry of the cell. In the designing of structural analogues modelled to inhibit some essential life systems of bacteria, many factors have to be taken into consideration in order to retain in the inhibitor the power to participate in a re¬ quired enzymic action, for instance Bell and Roblin and also Fildes and Rydon have demonstrated the importance of polar effects in bacterial inhibitors. Bell and Roblin, showed that sulphonamides in which the polarity of the SCb group approaches that of the COO ion of the p-aminobenzoic acid are the better inhibitors of those bacteria for which p-aminobenzoic acid is an essential metabolite. Sometimes the study of the metabolite itself leads to interesting information. Thus
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