Antimicrobial agent / Antibiotics – Chemical substances that are produced by microorganisms and which inhibit or kill other microorganisms

Selective toxicity – Toxic only to the microbial agent and not to the host cells.

Therapeutic Index = Toxic Dose / therapeutic Dose

Toxic dose – Dose that damages host cells

Therapeutic dose – Dose required for clinical treatment

Larger the toxic dose than the therapeutic dose, larger will be the therapeutic index of the drug. Higher the therapeutic index, safer will be the drug to the host.

A drug that is toxic to microbes but not to the eukaryotic cells of the host often has a greater selective toxicity and a higher therapeutic index.

Natural antibiotics – penicillin G and V, cephalosporin, vancomycin, teicoplanin, aminoglycosides, macrolides, tetracyclines

Synthetic antibiotics – chloramphenicol, sulphonamides, trimethoprim, quinolones and fluoroquinolones, isoniazid, dapsone

Semi-synthetic antibiotics – ampicillin, amoxicillin, carbenicillin, methicillin

Characterization of drugs based on:

  1. chemical structure
  2. spectrum:
    • Narrow spectrum – Effective against only a limited variety of pathogens
    • Broad spectrum – Effective against a large variety of pathogens
  3. target microbial group:
    • Antibacterial
    • Antiviral
    • Antiprotozoan
    • Antifungal
  4. activity:
    • Bactericidal – kill the pathogens, however, its activity is concentration dependent
    • Bacteriostatic – reversibly inhibit the growth of pathogens. If the drug is removed microbes start to grow again

MIC – Minimum Inhibitory Concentration. Minimum concentration of an antimicrobial agent required to inhibit the growth of a microorganism.

MLC – Minimum Lethal Concentration. Minimum concentration of an antimicrobial agent required to kill a microorganism.

For cidal drugs, the MLC is 2-4 times higher than MIC. For static drugs, the MLC is much higher than its MIC.

An antimicrobial agent may be static for one species but cidal for another. Bactericidal drugs are given under life threatening conditions, to immunocompromised patients whose immune system is too weak to eliminate the infection and when the infection needs to be eliminate rapidly. Static drugs work to stop the population growth after which the immune mechanism of the host takes care of the infection.

Some Important Facts

  • Paul Ehrlich – Father of modern chemotherapy
  • He named the chemical dyes “Magic Bullets”.
  • 1904 – Ehrlich found that the dye trypan red was active against trypanosome that causes African sleeping sickness. Hence, had a therapeutic use
  • Ehrlich and Sahachiro Hata – Found arsphenamine to be active against syphilis spirochete in rabbits
  • Arsphenamine was sold under the name Salvarsan
  • Gerard Domagk – Discovered Prontosil Red to protect mice completely from pathogenic Staphylococci and Streptococci. Prontosil red was later shown to be metabolized into sulphanilamide in the body
  • 1939 – Domagk received Nobel prize for the discovery of Sulphonamides or Sulfa drugs
  • 1920s – Alexander Fleming discovered lysozyme, an antibacterial substance in human tears
  • 1928 – Alexander Fleming discovered Penicillin produced by notatum that inhibited the growth of Staphylococcus aureus
  • Fleming, Florey, Chain – Received Nobel prize for the discovery and production of penicillin
  • 1944 – Streptomycin produced by Streptomyces griseus was discovered by Selman Waksman
  • 1952 – Waksman received Nobel prize for the discovery of streptomycin
  • Streptomycin was the first drug that could treat tuberculosis successfully
  • Some antibiotic used for microbiological research purpose are :
    • Actinomycin D (inhibits RNA synthesis)
    • Chloramphenicol (inhibits bacterial protein synthesis)
    • Cycloserine (inhibits bacterial peptidoglycan synthesis)
    • Nalidixic acid and Novobiocin (inhibits bacterial DNA synthesis)
    • Rifampin (inhibits bacterial RNA synthesis)
    • Cycloheximide (inhibits eukaryotic protein synthesis)
    • Polyoxin D (inhibits fungal cell wall chitin synthesis)
    • Mitomycin C (inhibits eukaryotic DNA synthesis)
    • Daunomycin (inhibits fungal RNA synthesis)
    • Cerulenin (inhibits fatty acid synthesis)

 

Antibacterial drugs

    • Inhibitors of Cell Wall Synthesis
      1. Penicillin
        • 6-aminopenicillanic acid is the precursor
        • Obtained from the fungus Penicillium notatum or chrysogenum
        • Penicillinase or beta lactamase inhibits the activity of penicillin
        • Structure resembles terminal D-Alanyl-D-Alanine of the peptide side chain that links peptidoglycan chains of the bacterial cell wall
        • Competitively inhibits transpeptidase enzyme. Hence, cell wall synthesis is blocked
        • Penicillin binds to Penicillin binding proteins (PBPs) which then activate autolytic enzymes
        • They may also stimulate bacterial holins which create holes through the plasma membrane leading to membrane leakage. Murein hydrolases could move through these holes and lyse the cell wall
        • Natural penicillins are narrow spectrum
        • Penicillin G is administered parenterally since it is labile to stomach acid
        • Penicillin v is administered orally
        • Semi-synthetic penicillins have broader spectrum

       

      1. Cephalosporin
        • Obtained from the fungus Cephalosporium
        • Possesses beta lactam ring
        • Broad spectrum
        • Structure resembles terminal D-Alanyl-D-Alanine of the peptide side chain that links peptidoglycan chains of the bacterial cell wall
        • Competitively inhibits transpeptidase enzyme. Hence, cell wall synthesis is blocked
        • 4 generations :
          • 1st – Inhibits gram positive bacteria
          • 2nd – Inhibits gram positive, gram negative and anaerobic bacteria
          • 3rd – Inhibits gram negative bacteria and those that can cross the blood brain barrier
          • 4th – Inhibits gram negative, gram positive and opportunistic bacteria

       

      1. Vancomycin
        • A glycopeptide antibiotic produced by Streptomyces orientalis (actinomycete)
        • The peptide part binds to the terminal D-Ala of the peptide side chain in bacterial murein and prevents the activity of transpeptidase enyme
        • Drug of last choice for Staphylococci and Enterococci

       

      1. Teicoplanin
        • A glycopeptide antibiotic produced by Actinoplanes teichomyceticus (actinomycete)
        • The peptide part binds to the terminal D-Ala of the peptide side chain in bacterial murein and prevents the activity of transpeptidase enyme
        • Fewer side effects than vancomycin

Continued to Part 2

actinomycinalexander flemingantibacterial drugsantibioticsantimicrobial agentsantimicrobialsbactericidalbactericidal drugsbacteriostaticbacteriostatic drugsbeta lactambeta lactamasebroad spectrumbroad spectrum antibioticscell wallcell wall synthesis inhibitorscephalosporinchloramphenicolinhibitors of cell wall synthesismagic bulletsMICminimum inhibitory concentrationminimum lethal concentrationMLCnalidixic acidnarrow spectrumnarrow spectrum antibioticsnovobiocinpenicillinrifampinselective toxicityselman waksmansulfonamidesulfonamidesteicoplanintherapeutic dosetherapeutic indextoxic dosetranspeptidasevancomycin
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