Inhibitors of folate biosynthesis

The human organism does not have the enzymes necessary for synthesizing folic acid which it needs. Folic acid must be supplied by the diet. Under these conditions, a pure inhibitor of the synthesis folic acid should not have many adverse effects in humans.

Various microorganisms, bacteria, Plasmodia, synthesize themselves folic acid and the inhibition of this synthesis inhibits their replication. Inhibitors of the synthesis of folic acid have antibiotic and antimalarial properties.

Folic acid can be regarded as constituted of a nucleus pterine, para-aminobenzoic acid, PABA, and one or more glutamate molecules. In absence of folate supply by the external medium, the microorganisms must synthesize it.

Inhibitors of the synthesis of folic acid like sulfonamides, sulfones and para-aminosalicylic acid are structural analogs of para-aminobenzoic acid with which they enter in competition for the synthesis of folic acid that they disturb. They inhibit dihydropteroate synthase, a microbial enzyme responsible of the incorporation of para-aminobenzoic acid in dihydropteroic acid, precursor of folic acid.


Sulfonamides are derivatives of para-amino-benzene sulfonamide. By inhibiting the activity of dihydropteroate synthase, they prevent the synthesis of folic acid necessary to the growth of certain bacteria. The micro-organisms sensitive to sulfonamides use PABA to synthesize their own folic acid and a supply of PABA from the culture medium can suppress the effects sulfonamides. The micro-organisms which can use folic acid from the external medium are not sensitive to sulfonamides.

A great number of micro-organisms were susceptible to sulfonamides, streptococci, meningococci, Hemophilus influenzae, Nocardia, Actinomyces, Clamydia trachomatis, certain strains of Plasmodium but, because the development of resistance, their medical use is now restricted to a few cases and many sulfonamides have been withdrawn from the market. This resistance is explained by different mechanisms, mainly an increased production of PABA by certain microorganisms. The sulfonamides used currently can be classified according to their pharmacokinetic characteristics.

The sulfonamides which are absorbed from the digestive tract diffuse throughout the body and can be used to treat general infections. Some of them are eliminated in the urine at very high concentration.

Sulfadiazine was used in the treatment of the infections caused by sensitive microorganisms like streptococci. Because of its short half-life, four to six intakes were needed every day. Because of the development of resistance it is not marketed any more in the majority of the countries, except for topical use as sulfadiazine-silver for example.

Sulfamethoxazole is used as a broad spectrum antibacterial, but, to avoid resistances, it is generally combined with trimethoprim, inhibitor of the DHFR (Bactrim*).

Sulfixoxazole, also called sulfafurazole, is used in combination with erythromycin for the treatment of infections caused by Hemophilus influenzae,

Sulfadoxine is used as an antimalarial agent, in combination with pyrimethamine, inhibitor of the DHFR (Fansidar*).

Sulfamethizole is a sulfonamide with urinary elimination. It is absorbed by digestive tract and diffuses throughout the body, but its essential feature is to be quickly eliminated by the kidney and to be present in the urine at very high concentration. It is used for the treatment of the urinary infections.

Sulfonamides such as sulfaguanadine which are not absorbed from the digestive tract after oral administration have been used for the treatment of gastrointestinal infections.

Sulfasalazine (Salazopyrin*) is hydrolyzed in the intestine into sulfapyridine, antibacterial sulfonamide and into 5-aminosalicylic acid, also called mesalazine or mesalamine, which has anti-inflammatory properties and is used for the treatment of inflammatory bowel diseases.

Sulfanilamide and sulfacetamide were used topically in the treatment of skin infections. Their local use can create a sensitizing at the origin of allergic reactions.

The adverse effects of sulfonamides, not very frequent, are blood disorders: leukopenia, agranulocytosis, and allergic disorders: haemolytic anemia and mucocutaneous reactions generally banal but sometimes severe, as Stevens-Johnson or Lyell syndromes for example.


The sulfone function R1-SO2-R2 is chemically close to that of sulfonamides. Dapsone, or diaminodiphenylsulfone, has the same mechanism of action that sulfonamides but its antibiotic activity affects primarily the leprosy bacillus which becomes resistant. Dapsone is slowly but almost completely absorbed from the digestive tract after oral administration. The prolonged use of dapsone, as necessary for the treatment of leprosy, induces certain of adverse effects:

Para-amino-salicylic acid or PAS

Para-amino-salicylic acid or PAS is active against Mycobacterium tuberculosis but it was not used any more in the treatment of tuberculosis because there were more effective drugs such as isoniazid, rifampin, ethambutol, pyrazinamide. But, because of the development of resistant tuberculosis, PAS can be again useful. The intra-bacterial penetration of PAS is passive and high concentrations are needed to obtain a bacteriostatic effect. PAS is, like sulfonamides, a competitive analog of para-amino-benzoic acid. It could, moreover, inhibit the synthesis of mycobactins which are chelating agents used by Mycobacterium tuberculosis to take iron from the external medium.

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