Inhibitors of Tetrahydrofolate Synthesis

Tetrahydrofolic acid (THF) is a co-enzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and 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 dihy-drofolate 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 folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and tri-methoprim.

Sulfonamides structurally resemble p-aminobenzoic acid (PABA), a precursor in bacterial DHF synthesis. As false substrates, sulfonamides competitively inhibit utilization of PABA, hence DHF synthesis. Because most bacteria cannot take up exogenous folate, they are depleted of DHF. Sulfonamides thus possess bacteriostatic activity against a broad spectrum of pathogens. Sulfon-amides are produced by chemical synthesis. The basic structure is shown in (A). Residue R determines the pharma-cokinetic properties of a given sulfon-amide. Most sulfonamides are well absorbed via the enteral route. They are metabolized to varying degrees and eliminated through the kidney. Rates of elimination, hence duration of effect, may vary widely. Some members are poorly absorbed from the gut and are thus suitable for the treatment of bacterial bowel infections. Adverse effects may include, among others, allergic reactions, sometimes with severe skin damage, displacement of other plasma protein-bound drugs or bilirubin in neo-nates (danger of kernicterus, hence contraindication for the last weeks of gestation and in the neonate). Because of the frequent emergence of resistant bacteria, sulfonamides are now rarely used.

Introduced in 1935, they were the first broad-spectrum chemotherapeutics.

Trimethoprim inhibits bacterial DHF reductase, the human enzyme being significantly less sensitive than the bacterial one (rarely bone marrow depression). A 2,4-diaminopyrimidine, tri-methoprim, has bacteriostatic activity against a broad spectrum of pathogens. It is used mostly as a component of co-trimoxazole.

Co-trimoxazole is a combination of trimethoprim and the sulfonamide sul-famethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual components. Resistant pathogens are infrequent; a bactericidal effect may occur. Adverse effects correspond to those of the components.

Although initially developed as an antirheumatic agent (p. 320), sulfasala-zine (salazosulfapyridine) is used mainly in the treatment of inflammatory bowel disease (ulcerative colitis and terminal ileitis or Crohn's disease). Gut bacteria split this compound into the sulfonamide sulfapyridine and mesala-mine (5-aminosalicylic acid). The latter is probably the anti-inflammatory agent (inhibition of synthesis of chemotactic signals for granulocytes, and of H2O2 formation in mucosa), but must be present on the gut mucosa in high concentrations. Coupling to the sulfon-amide prevents premature absorption in upper small bowel segments. The cleaved-off sulfonamide can be absorbed and may produce typical adverse effects (see above).

Dapsone (p. 280) has several therapeutic uses: besides treatment of leprosy, it is used for prevention/prophylaxis of malaria, toxoplasmosis, and actino-mycosis.

Folic acid

(Vitamin)

Dihydro-folic acid (DHF)

Sulfamethoxazole I y 12 hours

Folic acid

(Vitamin)

Dihydro-folic acid (DHF)

Trimoxazole

Sulfamethoxazole I y 12 hours

Dosing interval

Co-trimoxazole =

Combination of Trimethoprim | and Sulfamethoxazole

Synthesis of purines

Thymidine

Sulfasalazine (not absorbable) HOOC

7 days

Dosing interval

Co-trimoxazole =

Combination of Trimethoprim | and Sulfamethoxazole

Synthesis of purines

Thymidine

Bacterium

Human cell

Sulfasalazine (not absorbable) HOOC

Cleavage by intestinal bacteria

Mesalamine Sulfapyridine

(absorbable)

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