City College of San Francisco Microbiology 12

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The Activity of Antimicrobial drugs

Note:

This information is NOT intended as medical advice. Before taking any medication consult with a physician.

Antiviral & antiparasitic agents will be dealt with in separate lectures.

 Terminology related to antibiotics

The Principal of Selective Toxicity

This important concept was developed by Paul Ehrlich in the early 1900's while he studied dyes that stained microbial cells but not animal (eukaryotic) cells. Ehrlich realized this selectivity could be used to develop "magic bullets" against microbial pathogens which would leave the host unharmed. Ehrlich struck his target when "compound 606," an arsenical compound called Salvarsan proved effective for the treatment of syphilis.

What is an antibiotic?

An antibiotic is a natural substance produced by microbes that inhibits or kills other microbes. Only a few useful and natural sources of antibiotics have been identified from bacteria and fungi. For example, the fungi Penicillium and Cephalosporium give rise to penicillin and cephalosporins, respectively. Species of Bacillus provide us with the antibiotics polymyxin and bacitracin. Over half of all naturally occurring antibiotics are isolated from species of Streptomyces which are common soil bacteria. Currently most mass produced antibiotics are semi-synthetic derivatives of natural compounds.

Growth factor analogs (GFAs)

These drugs are are synthetic chemicals (manufactured by us) and not naturally produced by microbes. GFAs typically act as competitive inhibitors of essential biochemical pathways. The compounds typically mimic" important building blocks needed for microbial growth but are sufficiently different that the function of the growth factor in the cell is impeded. GFAs resembling DNA bases, amino acids and vitamins are currently in use. Sulfa drugs were the first GFA's to be identified and are discussed under the section headed "antimetabolites." Other GFAs are useful for treating a variety of viral and fungal infections.

Bactericidal drugs

Act by killing bacteria.

Bacteriostatic drugs

Act to suppress or inhibit bacterial replication sufficiently until the immune system can eliminate the organisms

Prophylactic drugs

Drugs taken to prevent a disease rather than treat an established infection

Synergism

Certain drugs work better together in combination compared to being used individually.

Antagonism

 Certain drugs may decrease the effectiveness of others, or prove toxic when taken in combination.Monotherapy

Taking a single agent to treat an infection

Combination therapy

Taking more than one drug to treat an infection. This is a common strategy used to treat certain infectious disease agents that are notoriously drug resistant such as HIV and Mycobacterium tuberculosis.

Patient compliance

The ability of a patient to adhere to their drug regimen and complete a course of therapy

Spectrum of activity

Narrow spectrum drugs

 Target a particular type of microbe. Use of narrow spectrum agents is preferable for treatment of specific infections and to minimize the possibility of selecting for drug resistant organisms.

Broad spectrum drugs

Act against a wide range of microorganisms.

 

 Ideal characteristics of antibiotics

• selective toxicity with minimal side effects to host
• easy to tolerate without a complex drug regimen
• bactericidal rather than bacteriostatic
• narrow spectrum rather than broad
• low cost of production & for consumer
• stable (shelf-life)
• adequate bioavailability: drug much reach adequate concentrations in relevant tissues or body sites

A single agent is unlikely to meet all of these criteria

Major targets of antibiotics:

• Cell wall
• Ribosomes
• Nucleic Acids
• Cell membrane
• Antimetabolites

Inhibitors of cell wall synthesis

1. B-lactams (Penicillins, Cephalosporins)

 Key features:

• Bactericidal
• Original penicillin G targets gram positives. Some semisynthetics have a broader spectrum of activity & can cross the outer membrane of gram negatives. Used to treat certain infections caused by staphylococci, streptococci, Neisseria, and spirochetes
• Cross peptidoglycan & bind to receptors called penicillin-binding proteins in the cell membrane
• The PBPs also act as "transpeptidases;" enzymes responsible for the terminal step in peptidoglycan synthesis. Transpeptidation involves the formation of peptide crosslinks. By binding to transpeptidases cell wall synthesis is brought to a halt.
• Autolysins (enzymes) are released from the cell that further degrade the cell wall
• Bacterial cell lyses and dies
• Resistance usually due to production of B-lactamases which cleave the B-lactam ring of the antibiotic.

2. Vancomycin

Key features:

• Bactericidal
• Narrow spectrum: target gram positives. Do not penetrate gram negative outer membrane. 
• Drug of choice for strains of Staphylococcus aureus that are resistant to most other antibiotics
• Glycopeptide isolated from soil bacterium
• Acts as a peptide analog. Inhibit transpeptidation by binding to the peptide portion of the cell wall molecule after it is exported out of the cell
• May also alter cell wall permeability.

3. Isoniazid (INH)

• Bacteriostatic
• Used in prophylaxis and treatment of tuberculosis (treatment involves combination therapy)
• Mechanism uncertain. Appears to inhibit mycolic acid synthesis
• Major toxicities may involve altered liver function.

Inhibitors of protein synthesis

30 S inhibitors ( Aminoglycosides, Tetracyclines)

 Aminoglycosides (Streptomycin, Kanamycin, Gentamicin)

• Bactericidal
• Primarily target gram negatives. Streptomycin was the first useful drug developed against tuberculosis
• Use has declined with development of semisynthetic penicillins. Generally considered "reserve" antibiotics if other drugs fail.
• Bind to 30S ribosomal subunit & inhibit protein synthesis by preventing peptide chain elongation
• Prolonged use can lead to kidney damage & hearing loss

Tetracyclines

• Bacteriostatic
• Structure comprised of four fused rings
• Used in the treatment of chlamydia, cystic acne and Lyme disease.
• Overuse of tetracyclines in animal livestock feed has promoted resistance to these antibiotics
• Most of the drug binds to the 30S subunit and blocks incoming aminoacyl-tRNAs from binding to the mRNA-ribosome complex.
• Prolonged usage can cause liver toxicity, pitting and discoloration of teeth

50 S inhibitors (Erythromycin, Chloramphenicol)

 Erythromycin

• Bacteriostatic
• A common alternative drug for individuals allergic to penicillin. Often given orally to children to treat staphylococcal & streptococcal infections. Effective treatment for Legionnaire's disease.
• Macrolide drug with complex ring structure
• Binds to 50 S ribosomal subunit & prevents translocation & peptide bond formation

 Chloramphenicol

• Bacteriostatic
• Bind s to 50 S ribosomal subunit & prevents peptide bond formation

Inhibitors of nucleic acid synthesis

Quinolones (Ciprofloxacin)

• Bactericidal (fast-acting)
• Broad spectrum: useful against bacteria that are resistant to other drugs and for bacteria that survive within phagocytes
• Inhibit the enzyme DNA gyrase which is responsible for supercoiling of DNA

 Rifampin

• Bactericidal
• Used (in combination) for the treatment of tuberculosis and Mycobacterium avium complex infections
• Inhibits RNA synthesis by binding to RNA polymerase
• Resistance develops quickly due to altered target enzyme

Inhibitors of cell membranes

Due to similarities with human cell membranes their are fewer drugs available against this target

Polymyxins

• Bactericidal
• Derive from soil bacterium Bacillus polymyxa
• Act on gram negatives. Used topically (with bacitracin) for treatment of skin infections with gram negatives like Pseudomonas .
• Bind to phospholipids and cause leakage of cell contents

Ergosterol inhibitors

These drugs are largely anti-fungal agents. Their selective target is ergosterol which replaces cholesterol as the major sterol component in eukaryotic cell membranes.

Two major classes of inhibitors exist:

Polyenes (include Amphotericin B, Nystatin)

• Bind to cell membrane ergosterol causing membrane leakage & altered membrane transport
• Amphotericin usually given IV to treat systemic fungal infections. Many unpleasant side effects
• Nystatin is used in the topical treatment of Candida vaginal & oral thrush infections

Azoles (miconazole, clotrimazole, ketakonazole)

• Broad antifungal activity by disrupting ergosterol synthesis.
• Many available without prescription. Used as topical agents to treat fungal skin infections and Candida yeast infections
• With increasing use drug resistance is being reported.

Antimetabolites

Trimethoprim and Sulfonamides

Each inhibit a particular enzyme involved in the bacterial pathway for production of tetrahydrofolic acid (THFA). THFA is an essential cofactor used in the synthesis of certain DNA and RNA bases and certain amino acids. Animal cells take in preformed folic acid in the diet and do not make their own THFA. Consequently, they are unaffected by the drugs that block the THFA pathway. The sulfonamides are structural analogs of PABA which is used by the first enzyme in the THFA pathway.