Folic Acid Inhibition

This section has briefly reviewed some of the sites thatantibacterial agents are known to attack. Numerous and varied, these sites show that a well planned combination of drugs within the same polymer chain have a definite possibility of intersecting. They also show that there are many combinations within which organotin compounds may inhibit bacterial growth. 

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PABA) incorporation into folic acid (inhibition of folate synthesis). In large proportion of Mycobacterium leprae infections e.g. in lepromatous leprosy, resistance can develop, so combination of dapsone, rifampicin and clofazimine is used in initial therapy. 

Carmody BJ, et al. Folic acid inhibits homocysteine-induced proliferation of human arterial smooth muscle cells. J Vase Surg 1999 30(6) I 121-1 128. 

Bacteria will make their own folic acid. Inhibiting this synthesis can be used as an antibacterial strategy. 

HUVEC converts Hey to thiolactone (a byproduct of Hey auto-oxi-dation). Folic acid inhibits this conversion protein homocysteinylation (indirect incorporation of Hey into protein) increases with increasing... 

The action of the sulphonamides is antagonized by p-aminobenzoic acid and they act by inhibiting the uptake and utilization of 1-aminobenzoic acid by bacterial cells, which require this as a precursor of folic acid. 

Bacteria require p-aminobenzoic acid to biosyn thesize folic acid a growth factor Structurally sul fanilamide resembles p-aminobenzoic acid and is mistaken for it by the bacteria Folic acid biosynthesis IS inhibited and bacterial growth is slowed suffi ciently to allow the body s natural defenses to effect a cure Because animals do not biosynthesize folic acid but obtain it in their food sulfanilamide halts the growth of bacteria without harm to the host... 

In addition to direct effects of chemical compounds on the fetus, metabolic disturbances in the mother, such as diabetes or hyperthermia, or deficiencies of calories or specific nutrients such as vitamin A, zinc, and folic acid may lead to teratogenesis. Compounds that inhibit placental functions may also induce malformations, e.g., by inhibiting placental circulation. For example, hydroxyurea disrupts the placental circulation and induces malformations. In addition, it also induces DNA damage. 

Several tetrahydroquinazoline analogs of folic acid were synthesized by Baker and co-workers as potential anticancer agents, and the substance (61), at 50 m/ g/ml, gave a 50% inhibition of growth of Streptococcus faecalis on a Flynn folic acid medium containing 3 m/i,g of folic 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. 

The finding that 2,4-diaminopyrimidines inhibit the growth of microorganisms by interfering with their utilization of folic acid led to an intensive search for antiinfective agents in this class of heterocyclic compounds. This work led to the develop-... 

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

Methotrexate belongs to the class of antimetabolites. As a derivative of folic acid it inhibits the enzyme dihydrofolate reductase resulting in a decreased production of thymidine and purine bases essential for RNA and DNA synthesis. This interruption of the cellular metabolism and mitosis leads to cell death. 

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

Deficiencies in nutrients such as folic acid and vitamin B12 may hinder this process of erythrocyte maturation.4,5 Folic acid and vitamin B12 are important nutrients required for the formation of DNA. In a setting where these nutrients are decreased, DNA synthesis is inhibited, and consequently, erythrocyte maturation also is inhibited.4,5 Poor diet can be a contributor to the deficiencies in these... 

Folic acid antagonist inhibits dihydrofolate reductase (DHFR) blocks reduction of folate to tetrahydrofolate inhibits de novo purine synthesis results in arrest of DNA, RNA, and protein synthesis... 

MTX interferes with the growth of cancer cells by inhibiting the metabolism of folic acid. Drug efficacy was evaluated in vitro by MTT assay, as described above, and by Trypan Blue exclusion. Trypan Blue is a non-vital dye excluded by viable cells, but selectively staining dead cells. According to Figure 13.7, higher suppression of cell... 

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

Trimethoprim Trimethoprim Inhibits folic acid synthesis by Used in combination with... 

The answer is c. (Hardman, pp 1058-1059. Katzung, pp 793-795.) Trimethoprim inhibits dihydro folic acid reductase. Sulfamethoxazole inhibits p-aminobenzoic acid (PABA) from being incorporated into folic acid by competitive inhibition of dihydropteroate synthase. Either action inhibits the synthesis of tetrahydrofolic acid. 

Patients receiving sulfasalazine should receive oral folic acid supplementation since sulfasalazine inhibits folic acid absorption. 

Methotrexate Folic acid analog cancer chemotherapy, arthritis Inhibits proliferation T-cell suppression granulocytopenia lymphocytopenia... 

Sulfa drugs inhibit bacterial folic acid synthesis... 

Sulfa drugs were the first important antibacterials. Sulfa drugs act by inhibiting bacterial folic acid synthesis. 

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