Sulphonamides, Trimethoprim and Related Drugs

SULPHONAMIDES,  TRIMETHOPRIM  AND RELATED  DRUGS

Sulphonamides were discovered by Domagk in 1935. It had been shown that a red azo dye, prontosil, had a curative effect on mice infected with β-haemolytic streptococci; it was subsequently found that in vivo, prontosil was converted into sulphanilamide (Figure 11.9A). The basis of the antimicrobial activity of the sulphonamides is their structural similarity to p-aminobenzoic acid (PABA) which is an integral part of the B vitamin, folic acid. In sensitive bacteria, sulphonamides compete with PABA with the result that folic acid synthesis is reduced. Because the vitamin is essential for the manufacture of nucleic acids (and other important biochemicals), this leads to a reduction in, or cessation of, bacterial growth.

Chemical modifications of sulphanilamide (see Figure 11.9A) gave compounds with higher antibacterial activity or special properties like prolonged activity. The drugs were extensively used from the 1930s to the 1970s, after which their popularity declined due to resistance development and the introduction of safer and more effective antibiotics. A few sulphonamides are still used in topical therapies(notably silver sulphadiazine for burns) and in veterinary medicine, while sulphadiazine itself remains available for the prevention of rheumatic fever. Dapsone (Figure 11.9B) is a sulphonamide derivative that has been used extensively in the past for the treatment of leprosy, but again, although still available and currently employed as part of a multidrug treatment for leprosy, its use has declined as a result of resistance development and the introduction of better antibiotics.

In the body, folic acid must be reduced to dihydrofolic acid and then tetrahydrofolic acid in order to become active, and it was discovered that a group of synthetic drugs called diaminopyrimidines could inhibit the enzymes responsible for this reduction. These dihydrofolate reductase inhibitors, of which trimethoprim (11.9C) is the most important, were found to act synergistically with sulphonamides because they blocked successive steps in the synthesis of reduced folic acid. Consequently trimethoprim was introduced in 1969 as a combination product with sulphamethoxazole (cotrimoxazole) for the treatment of urinary tract and, less commonly, respiratory infections. Unfortunately, the advantages of using the combination product were not as great as anticipated partly because pharmacokinetic differences between the two drugs resulted in relative concentrations in the body which were far from optimal for synergy. This, together with increasing evidence that the antibacterial activity of co-trimoxazole was due largely to the trimethoprim component with the more toxic sulphamethoxazole contributing little, lead to the use of trimethoprim alone from the mid 1970s. Co-trimoxazole is currently recommended only for treatment of pneumocystis pneumonia, toxoplasmosis and nocardiasis.

Trimethoprim remains one of the least expensive orally active agents available for the treatment of urinary tract infections, for which it is still widely prescribed, although it, too, is suffering from increasing resistance development and the trend is towards its replacement with fluoroquinolones (see section 6). Other trimethoprim analogues, notably tetroxoprim, have been introduced as antibacterial agents, but have not demonstrated significant advantages over trimethoprim itself. The other important diaminopyrimidine possessing antimicrobial activity is pyrimethamine. This is used in combination with sulphadoxine or other drugs for the treatment (but not any longer for the prophylaxis) of malaria. It is used on its own for the treatment of toxoplasmosis and pneumocystis pneumonia.