Dihydropteroic acid

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

There is another fundamental difference between folate utilization in microbial and mammalian cells. Bacteria and protozoa are unable to take up exogenous folate and must synthesize it themselves. This is carried out in a series of reactions involving first the synthesis of dihydropteroic acid from one molecule each of pteridine and p-aminobenzoic acid (PABA). Glutamic acid is then added to form DHF which is reduced by DHFR to THF. Mammalian cells do not make their own DHF, instead they take it up firm dietary nutrients and convert it to THF using DHFR. 

Sulphonamides are structural analogues of PABA. They competitively inhibit the incorporation of PABA into dihydropteroic acid and there is some evidence for their incorporation into false folate analogues which inhibit subsequent metabolism. The presence of excess PABA will reverse the inhibitory action of sulphonamides, as will thymine, adenine, guanine and methionine. However, these nutrients are not normally available at the site of infections for which the sulphonamides are used. 

Dienestrol, 102, 103 Diethyl carbamazine, 278 Diethylstilbestrol, 101 Diethylthiambutene, 106 Dihexyrevine, 36 Dihydralazine, 353 Dihydrocodeine, 288 Dihydropteroic acid, in bacterial metabolism, 121 Diketene, addition to imines,... 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid (see Chapter 44), pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofoUc acid, a reaction... 

Finally, sulfonamides can interfere with intermediary metabolism. Because of their structural similarity to para-aminobenzoic acid (PABA), they can function as competitive inhibitors for dihydropteroate synthase. The result is interruption of microbial synthesis of folic acid by blocking formation of the folic acid precursor dihydropteroic acid. Sensitive microorganisms are those that must synthesize their own folic acid. Conversely, resistant bacteria and normal mammalian cells are unaffected since they do not synthesize folic acid but use the preformed vitamin. 

Folate biosynthetic pathways in bacteria. The incorporation of p-aminobenzoic acid into 7,8-dihydropteroic acid is competitively inhibited by sulfanilamide. 

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. 

A number of sulphonamides and sulphones interrupt the synthesis of dihydropteroic acid by inhibiting the activity of the enzyme dihydropteroate synthetase or by antagonising the action of p-aminobenzoic acid (PABA), a metabolite essential for its biosynthesis. 

Several possibilities come to mind. One is that the sulfonamide actually forms a pteridinyl derivative such as I, which in turn may tend to reduce the availability of the pteridyl pyrophosphate ester D, and decrease the production of G. A condensation product of sulfamethoxazole and the pteridyl alcohol B was actually obtained, raising the possibility of a sulfonamide-containing imposter of dihydropteroic acid arising. A second viable possibility is to consider a tautometric equilibrium between the pteridine alcohol B and the aldehyde form C, which will very likely form the Schiff base derivative J, with the p-amino function of a sulfonamide. This would also lead to a pteridyl alcohol depletion from the path of the FH2 synthesis (Seydel, 1968). 

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-... 

Sulfonamides competitively inhibit dihydropteroate synthase, the bacterial enzyme responsible for the incorporation of ptaa-aminobenzoic acid (PABA) into dihydropteroic acid, the immediate precursor of folic acid (Figure 43—2). Sensitive microorganisms must synthesize their own folic acid, while bacteria that can use preformed folate are not affected. Mammalian cells require preformed folic acid and are not affected by sulfonamides. 

---