Folic acid sulfonamides inhibiting

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

FIGURE 2.3 By inhibiting the synthesis of folic acid, sulfonamides exert their antibacterial activity. 

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. 

Figure 46-1. Inhibitory effects of sulfonamides and trimethoprim on folic acid synthesis. Inhibition of two successive steps in the formation of tetrahydrofolic acid constitutes sequential blockade and results in antibacterial synergy. (Modified and reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

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. 

Sulfa drugs Sulfonamides Inhibit folic acid synthesis by Gram-positive and -negative... 

Thus sulfonamides are bacteriostatic drugs that inhibit bacterial growth by interfering with the microbial synthesis of folic acid. More specifically, sulfonamides block the biosynthetic pathway of folic acid synthesis, thus competitively inhibiting the transformation of p-aminobenzoic acid to folic acid (mediated by the enzyme dihydropteroate synthetase), which allows them to be considered as antimetabolites. 

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. 

B. Humans cannot synthesize folic acid (A) diet is their main source. Sulfonamides selectively inhibit microbially synthesized folic acid. Incorporation (B) of PABA into microbial folic acid is competitively inhibited by sulfonamides. The TMP-SMX combination is synergistic because it acts at different steps in microbial folic acid synthesis. All sulfonamides are bacteriostatic. Inhibition of the transpeptidation reaction (C) involved in the synthesis of the bacterial cell wall is the basic mechanism of action of (3-lac-tam antibiotics Changes in DNA gyrases (D) and active efflux transport system are mechanisms for resistance to quinolones. Structural changes (E) in dihydropteroate synthetase and overproduction of PABA are mechanisms of resistance to the sulfonamides. 

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

Sulfonamides are used for controlling urinary tract infections, acute and chronic lung infections (norcadiosis), protozoan infections of the nervous system (i.e., toxoplasmosis), and a variety of infections in humans and livestock. Their mode of activity is by inhibiting the multiplication of bacteria by competitively inhibiting para-aminobenzioc acid (PABA) in the folic acid metabolism cycle (O Neil et al., 2001). More specifically, they block the synthesis of folic acid in bacteria as the drugs are structurally similar to PABA. Folic acid is essential to the synthesis of amino acids and nucleic acids. In bacteria, folic acid is synthesized from PABA... 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

Sulfonamides (bacteriostatic inhibit bacterial folic acid synthesis)... 

The compound sulfanilamide exhibits a structural similarity to para-amino benzoic acid (PABA). Woods and Fields proposed the theory that sulfonamides, being structurally similar to PABA, inhibit bacterial folate synthetase so that folic acid is not formed which is needed for a number of metabolic reactions. Folic acid derived from PABA is essential for bacterial metabolism. Sulfonamides inhibit the enzyme folic acid synthetase which is... 

Sulfonamides are structural analogs of PABA that competitively inhibit bacterial synthesis of folic acid (see p. 371). Because purine synthesis requires THF as a coenzyme, the sulfa drugs slow down this pathway in bacteria. 

Relatively unambiguous monotonic SARs also occur where activity depends on the ionization of a particular functional group. A classic example is that of the antibacterial sulfonamides where activity is exerted by competitive inhibition of the incorporation of p-aminobenzoic acid into folic acid. The bcll-shapcd relationship is consistent with the sulfonamide acting as the anion but permeating into the cell as the neutral species... 

This substance inhibits the growth of bacteria by interfering with the synthesis of folic acid, 7, which is an essential substance for bacteria and animals alike. However, animals acquire folic acid from a normal diet, whereas bacteria have to synthesize it. Biosynthesis of folic acid is blocked by 4-aminobenzenesulfonamide, probably because of the structural similarity of the sulfonamide to 4-aminobenzoic acid, which is a normal ingredient in the biosynthesis of folic acid. The enzyme system involved apparently substitutes the sulfonamide for... 

FIGURE 33-2 Folic acid metabolism in bacterial cells. Certain antibacterial drugs [e.g., sulfonamides and trimethoprim] inhibit the dihydrofolate synthetase and reductase enzymes, thus interfering with DNA biosynthesis. 

Aminosalicylic acid (Paser, PAS) exerts its effects in a manner similar to the sulfonamide drugs that is, aminosalicylic acid is structurally similar to para-aminobenzoic acid (PABA) and inhibits folic acid synthesis by competing with PABA in tuberculosis... 

The sulfonamides include sulfadiazine, sulfamethizole, and similar agents (see Table 33-4). Sulfonamides interfere with bacterial nucleic acid production by disrupting folic acid synthesis in susceptible bacteria. Sulfonamide drugs are structurally similar to PABA, which is the substance used in the first step of folic acid synthesis in certain types of bacteria (see Fig. 33-2). Sulfonamides either directly inhibit the enzyme responsible for PABA utilization or become a substitute for PABA, which results in the abnormal synthesis of folic acid. In either case, folic acid synthesis is reduced, and bacterial nucleic acid synthesis is impaired. 

Mechanism of Action. Pyrimethamine blocks the production of folic acid in susceptible protozoa by inhibiting the function of the dihydrofolate reductase enzyme. Folic acid helps catalyze the production of nucleic and amino acids in these parasites. Therefore, this drug ultimately impairs nucleic acid and protein synthesis by interfering with folic acid production. The action of sulfadoxine and other sulfonamide antibacterial agents was discussed in Chapter 33. These agents also inhibit folic acid synthesis in certain bacterial and protozoal cells. 

In acute and chronic urinary tract infection, the combination of trimethoprim and sulfamethoxazole (Bactrim, Septra) exerts a truly synergistic effect on bacteria. The sulfonamide inhibits the utilization of p-amino-benzoic acid in the synthesis of folic acid (Figure 2.3), whereas trimethoprim, by inhibiting dihydrofolic acid reductase, blocks the conversion of dihydrofolic acid to tetrahydrofolic acid, which is essential to bacteria in the denovo synthesis of purines, pyrimidines, and certain amino acids. Because mammalian organisms do not synthesize folic acid and therefore need it as a vitamin in their daily diets, trimethoprim-sulfamethoxazole does not interfere with the metabolism of mammalian cells. 

Blockade of Sequential Steps in a Metabolic Sequence Trimethoprim-sulfamethoxazole is the best-known example of this mechanism of synergy (see Chapter 46 Sulfonamides, Trimethoprim, Quinolones). Blockade of the two sequential steps in the folic acid pathway by trimethoprim-sulfamethoxazole results in a much more complete inhibition of growth than achieved by either component alone. 

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... 

Competitive inhibition of folic acid synthesis by sulfonamides. 

Although folic acid is vital for human health, we don t have the enzymes to make it it s a vitamin, which means we must take it in our diet or we die. Bacteria, on the other hand, do make folic acid. This is very useful, because it means that if we inhibit the enzymes of folic acid synthesis we can kill bacteria but we cannot possibly harm ourselves as we don t have those enzymes. The sulfa drugs, such as sul-famethoxypyridazine or sulfamethoxazole, imitate p-aminobenzoic acid and inhibit the enzyme dihy-dropteroate synthase. Each has a new heterocyclic system added to the sulfonamide part of the drug. 

Tetrahydrofolic acid (THF) is a coenzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and are required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing it-more precisely DHF-ffom precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

Sulfonamides were the first group of chemotherapeutic agents used for the prevention or treatment of bacterial infections in humans. Sulfonamides (e.g., sulfisoxazole) act by inhibiting bacterial synthesis of folic acid, a chemical required for synthesis of nucleic acid and protein. These drugs competitively inhibit the first step in the synthesis of folic acid—the conversion of para-aminobenzoic acid into dihydrofolic acid. Because humans absorb preformed folic acid from food, sulfonamide inhibition has only a minimal effect on hiunan cells. 

The sulfonamides are a group of organic compounds with chemotherapeutic activity they are antimicrobial agents and not antibiotics. They have a common chemical nucleus that is closely related to PABA, an essential component in the folic acid pathway of nucleic acid synthesis. The sulfonamides are synergistic with the diaminopyrim-idines, which inhibit an essential step further along the folate pathway. The combination of a sulfonamide and a diaminopyrimidine is advantageous because it is relatively non-toxic to mammalian cells (less sulfonamide is administered) and is less likely to select for resistant bacteria. Only these so-called potentiated sulfonamides are used in equine medicine. These drugs are formulated in a ratio of one part diaminopyrimidine to five parts sulfonamide, but the optimal antimicrobial ratio at the tissue level is 1 20, which is achieved because the diaminopyrimidines are excreted more rapidly than the sulfonamides. 

The sulfonamides act as competitive enzyme inhibitors and block the biosynthesis of the vitamin folic acid in bacterial cells (Fig. 10.14). They do this by inhibiting the... 

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. 

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... 

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