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Sulfonamides—the power of artificial synthesized

1. Introduction of sulfonamides drugs

Sulfonamides are synthetic antimicrobial agents with a wide spectrum encompassing most gram-positive and many gram-negative organisms. These drugs were the first efficient treatment to be employed systematically for the prevention and cure of bacterial infections, and they are the most widely used antibacterial agents in veterinary medicine for their cheap cost and efficient performance in bacterial diseases.
Sulfonamides, as antimetabolites, compete with para-aminobenzoic acid (PABA) for incorporation into folic acid. The action of sulfonamides illustrates the principle of selective toxicity where some difference between mammal cells and bacterial cells is exploited. As we all know, all cells require folic acid for growth. In the human body, folic acid gets into cells by diffusion or transportation. However, when in the bacterial, these pathways do not work well for the existence of bacterial cell wall. Therefore, in actually, bacteria must synthesize folic acid from p-aminobenzoic acid for these.
The sulfonamides are derivatives of sulfanilamide, which is the nucleus common to all. The addition or substitution of various functional groups to the amino group or in which various substitutions on other amino groups result in compounds with varying physical, chemical, pharmacologic, and antibacterial properties. Although amphoteric, sulfonamides generally behave as weak organic acids and are much more soluble in alkaline aqueous solutions than in acidic solutions. Those of therapeutic interest have PKa values of 4.8-8.6. Water-soluble sodium or disodium salts are used for parenteral administration. In a mixture of sulfonamides, each component drug has its own solubility; therefore, a combination of sulfonamides is more water soluble than a single drug at the same total concentration. This is the basis of triple sulfonamide mixtures used clinically.

2. Character of structure

To date about 15000 sulfonamide derivatives, analogues, and related compounds have been synthesized. This has leaded to the discovery of many useful drugs which are effective for diuretics, antimalarial and leprosy agents, and antithyroid agents. The basic structure of sulfonamide cannot be modified if it is to be an effective competitive “mimic” for p-aminobenzoic acid. Essential structural features are the benzene ring with two substituents para to each other; an amino group in the fourth position; and the singly substituted 1-sulfonamido group.

structure of sulfonamides

3. Mechanism of action and resistance

3.1 Mode of action
The sulfonamides are structural analogues of para-aminobenzoic acid (PABA) and competitively inhibit dihydropterate synthetase, an enzyme that facilitates PABA as a substrate for the synthesis of dihydrofolic acid (folic acid). Dihydrofolate is a precursor for formation of tetrahydrofolate (folinic acid), an essential component of the coenzymes responsible for single carbon metabolism in cells. Sulfonamides are antimetabolites that substitute for PABA, resulting in blockade of several enzymes needed for the biogenesis of purine bases and other metabolic reactions necessary for formation of RNA. Protein synthesis, metabolic processes, and inhibition of growth and replication occur in organisms that cannot use preformed folate. The effect is bacteriostatic, although a bactericidal action is evident at the high concentrations that may be found in urine. Diaminopyrimidines such as trimethoprim inhibit dihydrofolate reductase, which is further into the folic acid synthesis pathway. The combination of a sulfonamide and a diaminopyrimidine results in synergistic, bactericidal actions on susceptible organisms; as such, the combination is referred to as a “potentiated” sulfonamide.
Sulfonamides are most effective in the early stages of acute infections when organisms are rapidly multiplying. They are not active against quiescent bacteria. Typically, there is a latent period before the effects of sulfonamide therapy become evident. This lag period occurs because the bacteria use existing stores of folic acid, folinic acid, purines, thymidine, and amino acids. Once these stores are depleted, bacteriostasis occurs. Bacterial growth can resume when the concentration of PABA increases or when the level of sulfonamide falls below an enzyme-inhibitory concentration. Because of the bacteriostatic nature of sulfonamides, adequate cellular and humoral defense mechanisms are critical for successful sulfonamide therapy when used as sole agents. Even potentiated sulfonamides, which are bactericidal, are time dependent in their antibacterial efficacy.

mode of action

3.2 Bacterial resistance
Resistance to sulfonamides is both chromosomally and plasmid mediated. Altered proteins such that affinity is reduced appears to be the most common mechanism of resistance. For example, in staphylococci, chromosomally mediated resistance reflects mutations in genes encoding for dihydropterate synthetase and plasmid-mediated resistance reflects mutations in dihydrofolate reductases, with the latter causing high-level resistance to trimethoprim. Staphylococci may have acquired some mechanisms of sulfonamide resistance from enterococci. Because sulfonamides act in a competitive fashion, overproduction of PABA can also preclude inhibition of dihydropterate synthetase. In addition, alternate pathways of folic acid synthesis may also contribute to low-level resistance.

4. Adverse effects and toxicity

Adverse reactions to sulfonamides may be due to hypersensitivity or direct toxic effects. Possible hypersensitivity reactions include urticarial, angioedema, anaphylaxis, skin rashes, drug fever, polyarthritis, hemolytic anemia, and agranulocytosis. Clinical signs of toxic effects include muscle weakness, ataxia, blindness, and collapse. In addition, several adverse effects have been reported after prolonged treatment, including bone marrow depression, hepatitis and icterus, peripheral neuritis and myelin degeneration in the spinal cord and peripheral nerves, photosensitization, stomatitis, conjunctivitis, and keratitis sicca.

5. Introduction of our products

100008 - Sulfonamides Rapid Test Kit
100015 - TriTest BTS Rapid Test Kit
500002 - Sulfonamides Rapid Test Kit (for meat)

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