Antimicrobial Drugs

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					Antimicrobial Drugs
            General Concepts
• Antibiotics: antibacterial agents
  – Naturally occurring (Penicllin)
  – Semi-synthetic: slight alterations to naturally
    occurring agents
  – Synthetics: synthesized
    in the laboratory
             General Concepts
• It is important that any antibiotic demonstrate
  selective toxicity.
   – The drug must be more toxic to a pathogen than a
     pathogen’s host.


• This selective toxicity is possible due to
  difference in structure or metabolism between
  the pathogen and the host.
          Thought Questions
THOUGHT QUESTION A: Can you think of any difference
  between a human host and a bacterial pathogen that
  would be a target for antibacterial agents?




THOUGHT QUESTION B: Why are antibacterial drugs
  much more common than antifungal, antiprotozoan, and
  antihelmintic drugs?
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
  Inhibition of Cell Wall Synthesis
• Peptidoglycan: alternating NAM and NAG
  subunit chains that are held together by peptide
  bridges
   – When reproducing and growing, bacteria must
     synthesize more NAG/NAM units to add.
             Beta()-lactams
• Prevent cross-linkage of NAM subunits
   – Example: Penicillin
Beta()-lactams
 Cephalosporins (beta()-lactams)
• Prevent cross-linkage of NAM subunits
• More stable, more easily absorbed, work on some
  gram (-)
   – Examples: methicillin and cephalosporin

                           EXAMPLES:
                           FIRST GENERATION:
                                  Keflex
                                  Duricef 
                           SECOND GENERATION:
                                  Ceclor 
                           THIRD GENERATION:
                                  Rocephin 
       Other cell wall inhibitors
• Vancomycin: interfere with specific bridges that link
  NAM subunits in Gram-positives.

• Bacitracin: blocks secretion of NAG and NAM from
  cytoplasm of Gram-positives.

• Isoniazid: block mycolic acid addition to cell walls
  as well as peptidoglycan production

THOUGHT QUESTION: Which bacterial genus
  would be most effected by Isoniazid?
          Thought questions
• If a patient comes in with an infection of a
  bacterium that is dormant, yet still causing
  infection, would these classes of
  antibiotics work?
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
   Inhibition of Protein Synthesis
                                        Eukaryotic
• Ribosomes are the major
  structure of a cell that caries out
  protein synthesis.

• Eukaryotic and prokaryotic
  ribosomes differ in size and
  structure                             Prokaryotic



THOUGHT QUESTION: Why is
 the bacterial ribosome a
 good target for antimicrobial
 drugs?
     Inhibition of Protein Synthesis
• There are two major subunits of the ribosome:
   – 30S subunit
   – 50S subunit
• Both a critical in reading codons and initiating protein
  synthesis.
• The 50S also forms peptide bonds between amino
  acids.
            Aminoglycosides
• change the shape of
  the 30S subunit.
   – Ex. streptomycin
     and gentomycin

• prevent amino acids
  from entering the
  ribosome at the 30S
  subunit.
   – Ex. tetracycline
            Chloramphenicol
• blocks 50S ribosome, preventing peptide bond
  formation.
                 Macrolides
• Bind to 50S ribosome.
• Prevent movement from one codon to the next,
  halting translation
• Ex. Erythromycin
         Thought Question
• On which bacteria, Gram-positive or
  Gram-negative, would these antibiotics be
  most effective?
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
  Disruption of cytoplasmic membranes
• Plasma membranes are
  phospholipid bi-layers that
  contain sterols.
   – Fungi contain a sterol
     called ergosterol; human
     membranes contain
     cholesterol
• Two anti-fungal drugs          1. CLOTRIMAZOLE
                                    (LOTRIMIN®),
  exploit this fact:
                                 2. MICONAZOLE
   – Polyenes attach to             (MICATIN®),
     ergosterol in the
                                 3. FLUCONAZOLE
     membrane.
                                    (DIFLUCAN®)
   – Azoles inhibit ergosterol
     synthesis
 Disruption of cytoplasmic membranes
• Polymyxin:
  – disturbs phospholipid bi-layers

  – Effective against Gram-
    negative bacteria
     • Ex. Pseudomonas

  – toxic to kidneys and is usually
    used for external pathogens
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
        Anti-Metabolic Agents
• Metabolism: all of the chemical reactions
  within a cell used to store or release
  energy.
  – Organisms often have unique metabolic
    pathways.

THOUGHT QUESTION: Is Glycolysis and
 the Krebs cycle a good target for these
 classes of drugs?
                Sulfonamides
• similar in structure to PABA, a chemical critical in
  the synthesis of nucleotides for DNA and RNA
  synthesis.
• the presence of sulfonamides shuts down DNA/RNA
  synthesis and, thus, protein synthesis.
              Sulfonamides
• Why is this an effective antibacterial agent?
  – Humans derive folic acids from our diet and
    convert them to THF.
 Amantadine and Rimantadine
• Block uncoating of viral particles by
  neutralizing the pH within the lysosome.

• Effective in fighting influenza type A virus.
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
 Inhibition of Nucleic Acid Synthesis
• many compounds called nucleotide analogs
  mimic normal nucleotides used to build DNA/RNA.

• these are incorporated into DNA and RNA and
  prevent further replication, transcription, or
  translation.

• Commonly used to fight viral replication in Herpes
  and HIV.
   – Ex. ACV and AZT
Inhibition of Nucleic Acid Synthesis
 Inhibition of Nucleic Acid Synthesis
• Quinolones attack DNA replication specifically by
  attacking an enzyme associated with DNA uncoiling
  (DNA gyrase).
   – no effects on eukaryotes or viruses



                     EXAMPLES:
                     CIPROFLOXACIN (Cipro)
                     OFLOXACIN
                     NORFLOXACIN
 Inhibition of Nucleic Acid Synthesis
• Rifampin: binds to bacterial RNA polymerase
  (enzyme used in transcription).
   – used to fight Mycobacterium tuberculosis
 Classification of Antimicrobial Drugs
1.   Inhibition of cell wall
     synthesis

2.   Inhibition of protein
     synthesis

3.   Disrupt cytoplasmic
     membrane

4.   Inhibit metabolism

5.   Inhibit DNA/RNA
     synthesis

6.   Block attachment
  Prevention of Virus Attachment
• Attachment analogs, typically sugar or
  protein analogs, block viral attachment to
  a host cell.

• Arildone is one antagonist used to block
  attachment of poliovirus and some
  common cold viruses.
   CLINICAL
CONSIDERATIONS
CLINICAL CONSIDERATIONS
1. Availability

2. Expense

3. Stability of Chemical

4. Non-toxic and non-allergenic

5. Selectively toxic against a wide range of
   pathogens
          Spectrum of Action
• Spectrum of Action: the number of different kinds
  of pathogens a drug acts against.
   – Narrow Spectrum and Broad-Spectrum Drugs
        Thought Question
What is the use of broad spectrum
antibiotics not always desirable? (Hint:
think of the role of normal microbiota).
     Effectiveness of Antibiotic
• Microbiologists conduct Kirby-Bauer tests to
  determine the effectiveness of an antibiotic.
  – a zone of inhibition is measured to determine
    the effectiveness of an antibiotic.
• An pathogen can be either:
  – resistant
  – intermediate
  – susceptible
            Safety and Side Effects
 1. Toxicity: many drugs have side effects.
        – Polymyxcins and aminoglycosides have
          toxic effects on kidneys, often fatal effects.
        – Pregnant women and specifically fetuses
          are at most risk.

Azole                                               tetracyline
         Safety and Side Effects
2. Allergies: many drugs trigger allergic responses.
   – Penicllin allergies occur in 0.1% of the
       population.

3.    Disruption of Normal Microbiota: death of
      normal microbiota may result in a secondary
      infection
     • Candida albicans (yeast) infection of vagina and
         mouth often increase during application of
         broad spectrum antibiotics.
     • These are considered superinfections due to
         uncontrolled growth.
         Safety and Side Effects
4.    Antibiotic resistant organisms
     • In the absence of antibiotics, resistant cells are
        less efficient in growth compared to normal
        cells.
     • In the presence of antibiotics, normal cells die,
        allowing for the resistant cells to take over a
        population due to less competition.
           Thought Questions
• QUESTION I: How can cells obtain antibiotic
  resistance?




• QUESTION II: Why do resistant strains of bacteria
  develop more often in hospitals and nursing homes?
• Examples of organisms that often require
  multiple antibiotic resistance include:
  – Staphylococcus
                            Vancomycin-resistant
                           Staphylococcus aureus

  – Enterococcus

  – Pseudomonas

  – Mycobacterium

  – Plasmodium

				
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