Examples of other antimetabolites

There are other antimetabolites in medical use apart from the sulfonamides. Two examples are trimethoprim and a group of compounds known as sulfones (Fig. 10.16). 

Trimethoprim is a diaminopyrimidine structure which has proved to be a highly selective, orally active, antibacterial, and antimalarial agent. Unlike the sulfonamides, it acts against dihydrofolate reductase—the enzyme which carries out the conversion of folic acid to tetrahydrofolate. The overall effect, however, is the same as with sulfonamides—the inhibition of DNA synthesis and cell growth. 

Dihydrofolate reductase is present in mammalian cells as well as bacterial cells, so we might wonder why trimethoprim does not affect our own cells. The answer is that trimethoprim is able to distinguish between the enzymes in either cell. Although this enzyme is present in both types of cell and carries out the same reaction, mutations over millions of years have resulted in a significant difference in structure between the two enzymes such that trimethoprim recognizes and inhibits the bacterial enzyme, but does not recognize the mammalian enzyme. 

Trimethoprim is often given in conjunction with the sulfonamide sulfamethoxazole (Fig. 10.17). The latter inhibits the incorporation of PABA into folic acid, while the former inhibits dihydrofolate reductase. Therefore, two enzymes in the one biosynthetic route are inhibited. This is a very effective method of inhibiting a biosynthetic route and has the advantage that the doses of both drugs can be kept down to safe levels. To get the same level of inhibition using a single drug, the dose level of that 

The sulfones are the most important drugs used in the treatment of leprosy. It is believed that they inhibit the same bacterial enzyme inhibited by the sulfonamides, i.e. dihydropteroate synthetase. 

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