Dihydropteroate synthetase inhibitors

The key enzymes involved in the biosynthesis of DHFA and THFA are dihy-dropteroate synthetase, dihydrofolate synthetase and dihydrofolate reductase [1-3]. Drugs that block the synthesis of dihydropteroic acid are known as dihydropteroate synthetase inhibitors (PABA antagonists) and those which control the reduction of DHFA to THFA are called dihydrofolate reductase (DHFR) inhibitors. Collectively these drugs are known as antifolates. 

Dihydropteroate synthetase inhibitor Dihydropteroate reductase inhibitor Product name Primary use... 

Animals are unable to synthesize folic acid (6.62) and must consume adequate quantities in their diets. Plants and bacteria, however, are able to make folic acid. The first step of this synthesis is catalyzed by dihydropteroate synthetase and reacts dihydroptero-ate diphosphate (6.69) and para-aminobenzoic acid (PABA, 6.70) (Figure 6.25). Because this pathway is not found in humans, inhibition of the reaction is a method to ultimately stop TMP synthesis in an invading bacterium while not impacting the infected host. The sulfonamides, often called sulfa drugs, are a class of antibiotic that exploits the folic acid pathway and inhibits dihydropteroate synthetase. Sulfa drugs bind in the same fashion as PABA and act as competitive inhibitors. The active form of the first sulfa drug is sulfanilamide (6.71). Sulfamethoxazole (6.72) is a sulfa drug that is widely prescribed today.26... 

A closer look at these events reveals that bacteria synthesize folic acid using several enzymes, including one called dihydropteroate synthetase, which catalyzes the attachment of p-aminobenzoic acid to a pteridine ring system. When sulfanilamide is present it competes with the p-amino-benzoic acid (note the structural similarity) for the active site on the enzyme. This activity makes it a competitive inhibitor. Once this site is occupied on the enzyme, folic acid synthesis stops and bacterial growth stops. Folic acid can also be synthesized in the laboratory. ... 

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim (one part). The reason for using this combination is based upon the in vitro finding that there is a sequential blockade of folic acid synthesis, in which the sulphonamide is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR (see Chapter 12). The optimum ratio of the two components may not... 

Inhibitors of dihydrofolate reductase. f Inhibitors of dihydropteroate synthetase. 

The two steps involved are the biosynthesis of dihydropteroic acid catalyzed by dihy-dropteroate synthetase and inhibited by sulfonamides and sulfones (Chapter 2), and the reduction of dihydrofolic acid by DHFR, which can be inhibited by MTX, PM, TM, and other DHFR inhibitors. Hitchings proposed such combinations, which ideally should pro-... 

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