Sulfonamide , synergism

The sulfones and sulfonamides synergize with the inhibitors of dihydrofolate reductase, and the combinations have been effective in controlling malaria, toxoplasmosis, and coccidiosis. Fansidar, a combination of sulfadoxine and pyrimethamine, has been successful in controlling some strains of chloroquine-resistant Plasmodium falciparum malaria (see Chapter 53 Antiprotozoal Drugs). However, reports of Fansidar resistance have increased in recent years. New inhibitors effective against the sulfonamide-resistant 7,8-dihydropteroate synthase are needed. 

It has been shown that a few sulfones and sulfonamides may be of interest as drugs for treating malaria. Experimental research uncovered the pronounced synergism between sulfonamides and chloroguanide and pyrimethamine. 

Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46-2). Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone. 

Pyrimethamine and trimethoprim reversibly inhibit the second step in the synthesis of folic acid by inhibiting the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid. The trimethoprim-binding affinity is much stronger for the bacterial enzyme than the corresponding mammalian enzyme, which produces selective toxicity. A powerful synergism exists between either pyrimethamine or trimethoprim and sulfonamides (e g., sulfemethoxazole and trimethoprim) because of sequential blockage of the same biosynthetic pathway. 

Even though the synergism observed with antifolate-sulfonamide combinations appears real, whether or not the mechanism is truly a sequential blockade is questionable. For example, it was shown that a potent DHFR inhibitor, 2,4-diaminopteroyl aspartate, is not synergistic with sulfamethoxazole. In addition, it was found that DHFR isolated from E. coli could be inhibited by sulfonamides, suggesting a multiple simultaneous inhibition of DHFR by both drugs. Curiously, it was also found that the TM potentiates sulfonamides that alone are resistant to the bacterium tested. 

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE The 2,4-diaminopyrimidines inhibit dihydrofolate reductase of plasmodia at concentrations far lower than those required to inhibit the mammalian enzymes. The dihydrofolate reductase in malaria resides on the same polypeptide chain as thymidylate synthase and is not upregulated in the face of inhibition, which contributes to the selective toxicity of the antifolates. Synergism between pyrimethamine and the sulfonamides or sulfones has been attributed to inhibition of two steps in an essential metabolic pathway. 

A synergistic interaction between these drugs is apparent even when microorganisms are resistant to sulfonamide, but maximal synergism occurs when microorganisms are sensitive to both drugs. 

Supra-additive interactions and potentiation appear to be much less common than antagonism and the simple additive interactions described above. Supra-additive (synergistic) interaction is said to occur if the result of interaction is greater than the sum of the drugs used alone the best example is the therapeutic synergism of certain antibiotic combinations such as sulfonamides and dihydrofolic acid reductase inhibitors such as trimethoprim. Potentiation is said to occur when a drug s effect is increased by another agent that has no such effect. The best example of this type of interaction is the therapeutic interaction of beta-lactamase inhibitors such as clavulanic acid with lactamase-susceptible penicillins. 

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