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Tag words: antibiotic, antimicrobial, antimicrobial agent, antibiotic resistance, penicillin, methicillin, vancomycin.









Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Antimicrobial Agents in the Treatment of Infectious Disease
(page 2)


(This chapter has 6 pages)

© Kenneth Todar, PhD

Antibiotics must have Selective Toxicity for the Microbe

Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically-useful. The reason for this is that only compounds with selective toxicity can be used clinically.

The selective toxicity of antibiotics means that they must be highly effective against the microbe but have minimal or no toxicity to humans. In practice, this is expressed by a drug's therapeutic index (TI)  -  the ratio of the toxic dose (to the patient) to the therapeutic dose (to eliminate the infection). The larger the index, the safer is the drug (antibiotic) for human use.

The selective toxicity of antibiotics is brought about by finding vulnerable targets for the drug in the microbe that do not exist in the animal (eucaryote) that is given the drug. Most antibiotics in clinical usage are directed against bacterial cell wall synthesis, bacterial protein synthesis, or bacterial nucleic acid synthesis, which are unique in some ways to bacteria.  For example, the beta lactam antibiotics (penicillin and its relatives) inhibit peptidoglycan synthesis in the cell wall. Humans have neither a cell wall nor peptidoglycan and so are unaffected by the action of the drug. Other antibiotics, including streptomycin and the tetracyclines, target bacterial protein synthesis because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eucaryotic organisms. Antibiotics such as the flouroqinolones (e.g. ciprofloxacin) inhibit procaryotic (not eucaryotic) DNA replication, and rifamycins inhibit bacterial (not eucaryotic) DNA transcription.

From a patient point of view, the most important property of an antimicrobial agent is its selective toxicity, i.e., that the agent acts in some way that inhibits or kills bacterial pathogens but has little or no toxic effect on the patient. 

Characteristics of Antibiotics

Antibiotics may have a cidal (killing) effect or a static (inhibitory) effect on a range of microbes. The range of bacteria or other microorganisms that is affected by a certain antibiotic is expressed as its spectrum of action. Antibiotics effective against procaryotes that kill or inhibit a wide range of Gram-positive and Gram-negative bacteria are said to be broad spectrum. If effective mainly against Gram-positive or Gram-negative bacteria, they are narrow spectrum. If effective against a single organism or disease, they are referred to as limited spectrum.

A clinically-useful antibiotic should have as many of these characteristics as possible.
 
-It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms.

-It should be nontoxic to the host and without undesirable side effects.

-It should be nonallergenic to the host.

-It should not eliminate the normal flora of the host.

-It should be able to reach the part of the human body where the infection is occurring.

-It should be inexpensive and easy to produce.

-It should be chemically-stable (have a long shelf-life).

-Microbial resistance is uncommon and unlikely to develop.


Kinds of Antimicrobial Agents and their Primary Modes of Action

The table below is a summary of thetypes or classes of antibiotics and their properties including their biological source, spectrum and mode of action.

Classes of Antibiotics and their Properties
Chemical class Examples Biological source Spectrum (effective against) Mode of action
Beta-lactams (penicillins and cephalosporins) Penicillin G, Cephalothin  Penicillium notatum and Cephalosporium species Gram-positive bacteria Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Semisynthetic beta-lactams
Ampicillin, Amoxicillin
Gram-positive and Gram-negative bacteria Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Clavulanic Acid Augmentin is clavulanic acid plus Amoxicillin Streptomyces clavuligerus Gram-positive and Gram-negative bacteria Inhibitor of bacterial beta-lactamases
Monobactams Aztreonam Chromobacterium violaceum Gram-positive and Gram-negative bacteria Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Carboxypenems Imipenem Streptomyces cattleya Gram-positive and Gram-negative bacteria Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly
Aminoglycosides Streptomycin Streptomyces griseus Gram-positive and Gram-negative bacteria Inhibits translation (protein synthesis)

Gentamicin Micromonospora species Gram-positive and Gram-negative bacteria esp. Pseudomonas Inhibits translation (protein synthesis)
Glycopeptides Vancomycin Amycolatopsis orientalisNocardia orientalis (formerly designated) Gram-positive bacteria, esp. Staphylococcus aureus Inhibits steps in murein (peptidoglycan) biosynthesis and assembly
Lincomycins Clindamycin Streptomyces lincolnensis Gram-positive and Gram-negative bacteria esp. anaerobic Bacteroides Inhibits translation (protein synthesis)
Macrolides Erythromycin, Azithromycin
Streptomyces erythreus Gram-positive bacteria, Gram-negative bacteria not enterics, Neisseria, Legionella, Mycoplasma Inhibit translation (protein synthesis)
Polypeptides Polymyxin Bacillus polymyxa Gram-negative bacteria Damages cytoplasmic membranes

Bacitracin Bacillus subtilis Gram-positive bacteria Inhibits steps in murein (peptidoglycan) biosynthesis and assembly
Polyenes Amphotericin Streptomyces nodosus Fungi (Histoplasma)
Inactivate membranes containing sterols

Nystatin Streptomyces noursei Fungi (Candida) Inactivate membranes containing sterols
Rifamycins Rifampicin Streptomyces mediterranei Gram-positive and Gram-negative bacteria, Mycobacterium tuberculosis Inhibits transcription (bacterial RNA polymerase)
Tetracyclines Tetracycline Streptomyces species Gram-positive and Gram-negative bacteria, Rickettsias Inhibit translation (protein synthesis)
Semisynthetic tetracycline Doxycycline
Gram-positive and Gram-negative bacteria, Rickettsias Ehrlichia, Borrelia Inhibit translation (protein synthesis)
Chloramphenicol Chloramphenicol Streptomyces venezuelae Gram-positive and Gram-negative bacteria Inhibits translation (protein synthesis)
Quinolones
Nalidixic acid
synthetic
Mainly Gram-negative bacteria Inhibits DNA
replication

Fluoroquinolones
Ciprofloxacin
synthetic

Gram-negative and some  Gram-positive bacteria (Bacillus anthracis)
Inhibits DNA replication

Growth factor analogs Sulfanilamide, Gantrisin, Trimethoprim
synthetic
Gram-positive and Gram-negative bacteria Inhibits folic acid metabolism (anti-folate)


Isoniazid (INH) synthetic

Mycobacterium tuberculosis Inhibits mycolic acid synthesis; analog of pyridoxine (Vit B6)


para-aminosalicylic acid  (PAS)
synthetic

Mycobacterium tuberculosis Anti-folate





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