Biological Sciences
Sulfa Drugs
Sulfa drugs, also known as sulfonamides, are a class of synthetic antibiotics that inhibit the growth of bacteria by interfering with the synthesis of folic acid, a key component for bacterial growth. They were the first effective treatment for bacterial infections and played a significant role in reducing mortality rates from infectious diseases. However, their use has declined due to the development of antibiotic resistance and the availability of more effective antibiotics.
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8 Key excerpts on "Sulfa Drugs"
eBook - ePub- Ruben Vardanyan, Victor Hruby(Authors)
- 2006(Publication Date)
- Elsevier Science(Publisher)
p -aminobenzoic acid, it “interferes” with the biosynthesis of folic acid. As a result, the “misled” enzymes construct a “false” molecule of folic acid, which is not able to carry out the vital function of true folic acid.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.Currently, various sulfanilamide drugs are used in medicine, the choice of which depends on various factors, but above all on the type of stimulant, course of the disease, speed in which the drug is absorbed from the gastrointestinal tract, the speed in which it is excreted, and its ability to diffuse into different organs and tissues.Sulfonamides have a broad spectrum of antimicrobial activity, including Staphylococcus aureus , nonenterococcal types of Streptococcus, Listeria monocytogenes, Nocardia, Neisseria, Haemophilius influenzae , enteric Gram-negative types of E. coli, Proteus mirabilis , and a few forms of anaerobic bacteria. Above all, sulfonamides are used for treating uncomplicated infections of the urinary tract, infections caused by Nocardia asteroids , streptococcal pharyngitis, menigococcal diseases, toxoplasmosis, and others.Resistance to such drugs does develop during long-term use. Bacterial resistance to sulfonamides can develop as a result of mutations expressed either in the overproduction of p
eBook - PDF- Nina Parker, Mark Schneegurt, Anh-Hue Thi Tu, Brian M. Forster, Philip Lister(Authors)
- 2016(Publication Date)
- Openstax(Publisher)
By inhibiting the enzyme involved in the production of dihydrofolic acid, sulfonamides block bacterial biosynthesis of folic acid and, subsequently, pyrimidines and purines required for nucleic acid synthesis. This mechanism of action provides bacteriostatic inhibition of growth against a wide spectrum of gram-positive and gram-negative pathogens. Because humans obtain folic acid from food instead of synthesizing it intracellularly, sulfonamides are selectively toxic for bacteria. However, allergic reactions to Sulfa Drugs are common. The sulfones are structurally similar to sulfonamides but are not commonly used today except for the treatment of Hansen’s disease (leprosy). Trimethoprim is a synthetic antimicrobial compound that serves as an antimetabolite within the same folic acid synthesis pathway as sulfonamides. However, trimethoprim is a structural analogue of dihydrofolic acid and inhibits a later step in the metabolic pathway (Figure 14.12). Trimethoprim is used in combination with the sulfa drug sulfamethoxazole to treat urinary tract infections, ear infections, and bronchitis. As discussed, the combination of trimethoprim and sulfamethoxazole is an example of antibacterial synergy. When used alone, each antimetabolite only decreases production of folic acid to a level where bacteriostatic inhibition of growth occurs. However, when used in combination, inhibition of both steps in the metabolic pathway decreases folic acid synthesis to a level that is lethal to the bacterial cell. Because of the importance of folic acid during fetal development, Sulfa Drugs and trimethoprim use should be carefully considered during early pregnancy. The drug isoniazid is an antimetabolite with specific toxicity for mycobacteria and has long been used in combination with rifampin or streptomycin in the treatment of tuberculosis.
- Kenneth Williamson, Katherine Masters(Authors)
- 2016(Publication Date)
- Cengage Learning EMEA(Publisher)
Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. 568 Macroscale and Microscale Organic Experiments On the basis of this hypothesis, sulfanilamide was tested and found to be the active substance. Because sulfanilamide had been synthesized in 1908, its manufacture was not protected by patents, so the new drug and thousands of its derivatives were rapidly synthesized and tested. When the R group in sulfanilamide is replaced with a heterocyclic ring system—for example, pyridine, thiazole, diazine, merazine, and so on—the sulfa drug so produced is often faster acting or less toxic than sulfanilamide. Although they have been supplanted for the most part by antibiotics of microbial origin, these drugs still find wide application in chemotherapy. Unlike that of most drugs, the mode of action of the Sulfa Drugs is now completely understood. Bacteria must synthesize folic acid for growth. Higher animals, like humans, do not synthesize folic acid and hence must acquire it in their food. Sulfanilamide inhibits the formation of folic acid, stopping the growth of bacteria. This process is highly selective because the synthesis of folic acid does not occur in humans, so only bacteria are affected. A closer look at these events reveals that bacteria synthesize folic acid using several enzymes, including one called dihydropteroate synthetase, which catalyzes the attachment of p -aminobenzoic acid to a pteridine ring system. When sulfanilamide is present, it competes with the p -aminobenzoic acid (note the structural similarity) for the active site on the enzyme.
eBook - PDF- Mark A. Simmons(Author)
- 2020(Publication Date)
- Thieme(Publisher)
Examples include purine and pyrimidine analogues used in cancer or antiviral chemotherapy, as well as the sulfonamide antibacterial drugs that are discussed in this section. The ultimate effects of these antimetabolites may be exerted on nucleic acids, proteins, and cell walls. 29.9.1 Sulfonamides Sulfamethoxazole/Trimethoprim and Sulfadiazine Mechanism of Action Sulfonamides are structurally similar to p-aminobenzoic acid (PABA). They inhibit the synthesis of dihydrofolic acid in microbes that must synthesize dihydrofolic acid from PABA (▶ Fig. 29.10). Dihydrofolic acid is then reduced to form tetrahydrofolic acid by dihydrofolate reductase. This is required for the synthesis of purines and pyrimidines and amino acids. They are bacteriostatic at concentrations achieved in most body tissues and fluids, but bactericidal concentrations may be found in the urine. Trimethoprim is used in combination with sulfamethoxazole. It causes selective inhibition of bacterial dihydrofolate reductase. Spectrum ● Broad spectrum. ● Effective against most gram-positive bacteria (e.g., MRSA, MSSA, E. faecalis, E. faecium) and many gram-negative bacteria (e.g., H. influenza, P. mirabilis, E. coli, Klebsiella, Enterobacter , Serratia). ● No activity against anaerobes. ● Sulfamethoxazole in combination with trimethoprim is also active against Nocardia spp., Pneumocystis jiroveci, and L. monocytogenes. Pharmacokinetics ● Sulfonamides are readily absorbed after oral administration. ● Sulfonamides are widely distributed in the body and have a good CNS penetration. ● Sulfonamides are eliminated in the urine. Uses ● Treatment of urinary tract infections. ● Treatment of pneumocystis pneumonia. ● Treatment of uncomplicated respiratory infections. Side Effects ● The most common adverse effects of sulfonamides are nausea and vomiting and hypersensitivity reactions (rash and pruritus).
eBook - PDF- L Bryan(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
Thus, while it is possible to discuss sulfonamides in isolation, consideration of the antibacterial DHFR inhibitors is best done in conjunction with the sulfonamides. When sulfonamides were first introduced in the late 1930s, they were broad-spectrum antibiotics. Most bacteria of pathogenic importance were sensitive, being inhibited by the concentrations of these drugs attainable in the bloodstream after the therapeutic dose was administered. Impor-tant exceptions were Pseudomonas aeruginosa and Streptococcus fae-calis, no strains of which are inhibited by blood levels of sulfonamides. The earliest sulfonamides, such as sulfanilamide and sulfapyridine, were soon replaced by compounds with higher intrinsic activity and fewer side effects; the only important difference between the sulfonamides pres-ently on the market lies in their pharmacokinetic behavior. All sul-fonamides (with the exception of Marfanil, which is an inhibitor of car-bonic anhydrase) have the same mode of action, and there is complete cross-resistance between them. As resistance to them has increased and as other antibacterial agents have appeared, the clinical importance of the sulfonamides has diminished rather rapidly. Today they are reserved for a small number of indications, such as urinary infections, removal of the Hydroxymethylpteridine + PAB DPS Su Dihydropteroate Dihydrofolate DHFR Tm Tetrahydrofolate Deoxyuridylate thymidylate synthetase TVW^-Methylene tetrahydrofolate^ ^>Thymidylate Fig. 1. Biosynthesis of thymidylate in normal bacteria. Enzymes are italicized. Su = sulfonamide, Tm = trimethoprim, PAB = /?-aminobenzoate, DPS = dihydropteroate synthe-tase, and DHFR = dihydrofolate reductase. 6. ANTIBACTERIAL ANTIFOLATE AGENTS 175 meningococcal carrier state, and in ulcerative colitis. They are now, how-ever, very widely used in combination with trimethoprim. Trimethoprim was specifically designed to inhibit bacterial DHFR while not affecting the enzyme from the mammalian cell.
eBook - PDF- Mark A. Simmons(Author)
- 2011(Publication Date)
- Thieme(Publisher)
— Irreversible damage to developing cartilage has been observed in studies with young ani -mals; therefore, fluoroquinolones are not recommended for patients younger than 18 years or for use in pregnancy. 29.4 Inhibitors of Folate Metabolism (Antimetabolites) Antimetabolites are substances that have structural similarity to substrates used in interme -diary metabolism of the cell and that compete for enzymatic binding sites. Examples include purine and pyrimidine analogs used in cancer or antiviral chemotherapy, as well as the sul -fonamide antibacterial drugs that are discussed in this section. The ultimate effects of these antimetabolites may be exerted on nucleic acids, proteins, and cell walls. Sulfonamides (Sulfas) Sulfacytine, Sulfadiazine, Sulfamethizole, Sulfisoxazole, and Sulfamethoxazole Mechanism of action. Sulfonamides are structurally similar to p -aminobenzoic acid (PABA). They inhibit the synthesis of dihydrofolic acid in microbes that must synthesize dihydrofolic acid from PABA ( Fig. 29.10 ). Dihydrofolic acid is then reduced to form tetrahydrofolic acid by di -hydrofolate reductase. This is required for the synthesis of purines and pyrimidines and amino acids. They are bacteriostatic at concentrations achieved in most body tissues and fluids, but bactericidal concentrations may be found in the urine. Spectrum. The sulfonamides are broad-spectrum agents. — Effective against most gram-positive bacteria, many gram-negative bacteria, Nocardia, Ac-tinomyces, Chlamydia, and Plasmodium Pharmacokinetics — Sulfonamides are readily absorbed after oral administration. — Sodium salts may be given intravenously, but they are strongly alkaline and cause pain and tissue sloughing if extravasated (i.e., if the drug leaks into surrounding tissue). Antimicrobial Drugs 304 Fig. 29.9 ▶ Antibacterial drugs acting on DNA.
- Bernard R. Jones(Author)
- 2013(Publication Date)
- Butterworth-Heinemann(Publisher)
A drug with bacteriostatic action does not directly kill the organism, but blocks, or interferes with, its metabolism and thus weakens it and prevents it multiplying, so enabling the body's natural defence mechanism to overcome it. A bactericidal drug is capable of actually kilhng the organism. It should be noted that some drugs are bacteriostatic in moderate dosage and bactericidal in high. The recognition of the organism responsible for an infection is the result of meticulous work by the laboratory technician, and will involve isolating the organism (provided the appropriate specimen of urine, faeces, pus or sputum, for example, is available), growing it speedily in a suitable medium to enable complete microscopic, etc., examination, and finally testing against it the various anti-infective agents available, such as are discussed in this Chapter. His report will then identify the organism and indicate to the doctor the drug, or drugs, best suited to cope with the infection. Now to discuss the drugs themselves. CHEMOTHERAPEUTIC DRUGS The word chemotherapy is self-explanatory, chemo referring to the chemical nature of the drug, and therapy meaning treatment; thus chemotherapeutic drugs are chemicals which are used in the treatment of infection. An important point that needs adding is that they can be introduced into the system without undue toxic effect upon the patient. The best-known group under this heading is the Sulphonamides, sometimes called the sulpha drugs. Their introduction in 1936 112 PHARMACOLOGY FOR STUDENT NURSES initiated the era of chemotherapy, whereby it became possible for tablets or injections of a drug to be given to the patient, to be then absorbed and carried in the circulation to the site of infection, finally to weaken the organism responsible and so enable the natural defence mechanism of the body to complete the process. Note that the action is bacteriostatic. The first sulphouamide was effective mainly in streptococcal and E.
eBook - ePubChemistry and Medicines
An Introductory Text
- James R Hanson(Author)
- 2019(Publication Date)
- Royal Society of Chemistry(Publisher)
1 unit to uracil to form thymidine, a major component of the nucleic acids. In humans, folic acid is an essential dietary factor which is obtained from food. It is not biosynthesized by man. Consequently, the sulfonamides have no direct effect on folic acid in man but only on the production of folic acid in bacteria.The conversion of dihydrofolic acid 6.22 to tetrahydrofolic acid 6.24 is inhibited by another anti-bacterial agent, trimethoprim 6.23. A combination therapy of sulfamethoxazole 6.19 and trimethoprim (co-trimazole) has been particularly useful in combating resistance. If a bacterium develops resistance to sulfamethoxazole, it is killed by trimethoprim before it can replicate and so the resistance cannot be passed on. The enzyme dihydrofolate reductase has been crystallized and its X-ray crystal structure has been determined. The structure of the enzyme containing bound trimethoprim has also been determined.6.6 THE PENICILLINS
The observation by Fleming in 1928 of the antibiosis by the fungus Penicillium notatum , a chance contaminant of a culture of a Staphylococcus species proved to be one of the major discoveries of medicinal chemistry. The isolation of the penicillin antibiotics and the determination of their structure required a major microbiological and chemical effort in the days before spectroscopy played a major role in structure elucidation.The fungus Penicillium notatum produced a mixture of related compounds that were not particularly stable and which possessed what at that time, was an unknown ring system 6.25. The work was facilitated by the discovery in the USA of a higher-yielding strain of another fungus, Penicillium chrysogenum . The penicillins were shown to possess a common core and to differ from each other in the nature of the side chain. Their valuable antibiotic properties were demonstrated in the early years of the Second World War with a number of trials being conducted in 1941. These trials provided the stimulus for the major effort required to study the chemistry of the penicillins. Their structure was solved in 1945 by a combination of chemical and X-ray crystallographic work. A significant further advance came in 1959 with the development of enzymatic methods for isolating the core of the penicillins, 6-aminopenicillanic acid 6.28 from the major fermentation products, penicillins G 6.26 and V 6.27.
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