Chemotherapy of Tuberculosis and the Mode of Action of the Sulfonamide Compounds

¹ Director, Institute of Pathology, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania

In one of the sulfones is to be found the first chemotherapeutic agent against tuberculosis that has sufficient promise experimentally to justify a thorough-going trial clinically.

As regards the difficult problem concerning the mode of action of the sulfonamide compounds generally, it is becoming clearer that their biochemical effects are such as to interfere with the nutrition of the bacteria.

This they do by damaging their enzyme systems. Theoretically, this can come about in at least two ways; they may inactivate certain enzymes per se, or they may block enzyme action by interfering with the coenzymes.

Thus, the catalase-peroxydase system of enzymes can be inactivated by certain intermediate products of the oxidation of sulfanilamide. Hydroxylamine, or some related form, is perhaps the best example of this possibility.

On the other hand, sulfathiazole, presumably by virtue of the chemical constitution of its thiazole group, can interfere with the synthesis of co-zymase, a growth factor indispensable for the nutrition of the staphylococcus. Inasmuch as we are dealing with oxidation-reduction mechanisms, it is conceivable that these separate biochemical functions are complementary, at least in some instances. However, there is as yet no direct evidence on the point.

Anti-enzymatic action is likewise responsible for certain of the toxic effects of these drugs. Thus, the acidosis produced by sulfanilamide is referable to the inhibition of the enzyme, carbonic anhydrase, while the cyanosis is referable to a similar, if not identical, effect on hemoglobin. That is to say, it is partially oxidized to methemoglobin by the toxic NO₂ and NO derivatives of the free amino group of sulfanilamide.

Finally, certain of the sulfonamide compounds, such as sulfathiazole, seem capable of stimulating the rate of oxygen consumption of the body tissues, either as a whole or, in some instances, individual tissues. This all suggests that the effect of sulfathiazole on localized infections and on wound healing where no infection is involved, is due in part to an increase in tissue resistance.