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Antibiotic

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These are substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentrations. This definition excludes other natural substances which also inhibit microorganisms but are produced by higher forms (e.g. antibodies) or even those produced by microbes but are needed in high concentrations (ethanol, lactic acid, H2O2).

Initially the term ‘chemotherapeutic agent’ was restricted to synthetic compounds, but now since many antibiotics and their analogues have been synthesized, this criterion has become irrelevant; both synthetic and microbiologically produced drugs need to be included together. It would be more meaningful to use the term Antimicrobial agent (AMA) to designate synthetic as well as naturally obtained drugs that attenuate microorganisms.

The history of chemotherapy may be divided into 3 phases.

(a) The period of empirical use: of ‘mouldy curd’ by Chinese on boils, chaulmoogra oil by the Hindus in leprosy, chenopodium by Aztecs for intestinal worms, mercury by Paracelsus (16th century) for syphilis, cinchona bark (17th century) for fevers.

(b) Ehrlich’s phase of dyes and organometallic compounds (1890–1935): With the discovery of microbes in the later half of 19th century and that they are the cause of many diseases; Ehrlich toyed with the idea that if certain dyes could selectively stain microbes, they could also be selectively toxic to these organisms. He tried methylene blue, trypan red, etc. He developed the arsenicals—atoxyl for sleeping sickness, arsphenamine in 1906 and neoarsphenamine in 1909 for syphilis. He coined the term ‘chemotherapy’ because he used drugs of known chemical structure (that of most other drugs in use at that time was not known) and showed that selective attenuation of infecting parasite was a practical proposition.

(c) The modern era of chemotherapy was ushered by Domagk in 1935 by demonstrating the therapeutic effect of Prontosil, a sulfonamide dye, in pyogenic infection. It was soon realized that the active moiety was paraamino benzene sulfonamide, and the dye part was not essential. Sulfapyridine (M & B 693) was the first sulfonamide to be marketed in 1938.

The phenomenon of antibiosis was demonstrated by Pasteur in 1877: growth of anthrax bacilli in urine was inhibited by air-borne bacteria. Fleming (1929) found that a diffusible substance was elaborated by Penicillium mould which could destroy Staphylococcus on the culture plate. He named this substance penicillin but could not purify it. Chain and Florey followed up this observation in 1939 which culminated in the clinical use of penicillin in 1941. Because of the great potential of this discovery in treating war wounds, commercial manufacture of penicillin soon started.

In the 1940s, Waksman and his colleagues undertook a systematic search of Actinomycetes as source of antibiotics and discovered streptomycin in 1944. This group of soil microbes proved to be a treasure-house of antibiotics and soon tetracyclines, chloramphenicol, erythromycin and many others followed. All three groups of scientists, Domagk, Fleming-Chain-Florey and Waksman received the Nobel Prize for their discoveries.

In the past 40 years emphasis has shifted from searching new antibiotic producing organisms to developing semisynthetic derivatives of older antibiotics with more desirable properties or differing spectrum of activity. Few novel synthetic AMAs, e.g. fluoroquinolones, oxazolidinones have also been produced.

CLASSIFICATION

Antimicrobial drugs can be classified in many ways:

  • Chemical structure
  1. Sulfonamides and related drugs: Sulfadiazine and others, Sulfones—Dapsone (DDS), Para aminosalicylic acid (PAS).
  2. Diaminopyrimidines: Trimethoprim, Pyrimethamine.
  3. Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin, Gatifloxacin, etc.
  4. β-Lactam antibiotics: Penicillins, Cephalosporins, Monobactams, Carbapenems.
  5. Tetracyclines: Oxytetracycline, Doxycycline, etc.
  6. Nitrobenzene derivative: Chloramphenicol.
  7. Aminoglycosides: Streptomycin, Gentamicin, Amikacin, Neomycin, etc.
  8. Macrolide antibiotics: Erythromycin, Clarithromycin, Azithromycin, etc.
  9. Lincosamide antibiotics: Lincomycin, Clindamycin.
  10. Glycopeptide antibiotics: Vancomycin, Teicoplanin.
  11. Oxazolidinone: Linezolid.
  12. Polypeptide antibiotics: Polymyxin-B, Colistin, Bacitracin, Tyrothricin.
  13. Nitrofuran derivatives: Nitrofurantoin, Furazolidone.
  14. Nitroimidazoles: Metronidazole, Tinidazole, etc.
  15. Nicotinic acid derivatives: Isoniazid, Pyrazinamide, Ethionamide.
  16. Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin.
  17. Azole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole.
  18. Others: Rifampin, Spectinomycin, Sod. fusidate, Cycloserine, Viomycin, Ethambutol, Thiacetazone, Clofazimine, Griseofulvin.
  • Mechanism of action
  1. Inhibit cell wall synthesis: Penicillins, Cephalosporins, Cycloserine, Vancomycin, Bacitracin.
  2. Cause leakage from cell membranes: Polypeptides—Polymyxins, Colistin, Bacitracin. Polyenes—Amphotericin B, Nystatin, Hamycin.
  3. Inhibit protein synthesis: Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid.
  4. Cause misreading of m-RNA code and affect permeability: Aminoglycosides—Streptomycin, Gentamicin, etc.
  5. Inhibit DNA gyrase: Fluoroquinolones— Ciprofloxacin and others.
  6. Interfere with DNA function: Rifampin, Metronidazole.
  7. Interfere with DNA synthesis: Acyclovir, Zidovudine.
  8. Interfere with intermediary metabolism: Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine, Ethambutol.
  • Type of organisms against which primarily active
  1. Antibacterial: Penicillins, Aminoglycosides, Erythromycin, etc.
  2. Antifungal: Griseofulvin, Amphotericin B, Ketoconazole, etc.
  3. Antiviral: Acyclovir, Amantadine, Zidovudine, etc.
  4. Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, Diloxanide, etc.
  5. Anthelmintic: Mebendazole, Pyrantel, Niclosamide, Diethyl carbamazine, etc.
  • Spectrum of activity
  1. Narrow-spectrum: Penicillin G, Streptomycin, Erythromycin.
  2. Broad-spectrum: Tetracyclines, Chloramphenicol.
  • Type of action
  1. Primarily bacteriostatic: Sulfonamides, Erythromycin, Tetracyclines, Ethambutol, Chloramphenicol, Clindamycin, Linezolid.
  2. Primarily bactericidal: Penicillins, Cephalosporins, Aminoglycosides, Vancomycin, Polypeptides, Nalidixic acid, Rifampin, Ciprofloxacin, Isoniazid, Metronidazole, Pyrazinamide, Cotrimoxazole.
  • Antibiotics are obtained from
  1. Fungi: Penicillin, Griseofulvin, Cephalosporin.
  2. Bacteria: Polymyxin B, Tyrothricin, Colistin, Aztreonam, Bacitracin.
  3. Actinomycetes: Aminoglycosides, Macrolides, Tetracyclines, Polyenes, Chloramphenicol.




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