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Antimicrobial Drugs ©2011

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					Antimicrobial Drugs




   ©2011 prasit83.blogspot.com. All rights
               reserved.
                 General Concepts
• Antibiotics: antibacterial agents
   – Naturally occurring (Penicllin)
   – Semi-synthetic: slight alterations to naturally occurring
     agents
   – Synthetics: synthesized
     in the laboratory




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                                reserved.
                 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.




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                                reserved.
             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?




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                               reserved.
     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

                           ©2011 prasit83.blogspot.com. All rights
                                       reserved.
     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

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                                       reserved.
     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.




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               Beta()-lactams
• Prevent cross-linkage of NAM subunits
   – Example: Penicillin




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Beta()-lactams




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    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 

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                               reserved.
         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?

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            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?




                 ©2011 prasit83.blogspot.com. All rights
                             reserved.
     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

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                                       reserved.
     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

THOUGHT QUESTION: Why is the
  bacterial ribosome a good target                             Prokaryotic
  for antimicrobial drugs?




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         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.




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                                reserved.
               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


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               Chloramphenicol
• blocks 50S ribosome, preventing peptide bond
  formation.




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                   Macrolides
• Bind to 50S ribosome.
• Prevent movement from one codon to the next, halting
  translation
• Ex. Erythromycin




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           Thought Question
• On which bacteria, Gram-positive or Gram-
  negative, would these antibiotics be most
  effective?




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                           reserved.
     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

                           ©2011 prasit83.blogspot.com. All rights
                                       reserved.
     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 exploit this
  fact:
   – Polyenes attach to ergosterol                         1. CLOTRIMAZOLE
     in the membrane.                                         (LOTRIMIN®),
   – Azoles inhibit ergosterol
     synthesis                                             2. MICONAZOLE
                                                              (MICATIN®),
                                                           3. FLUCONAZOLE
                                                              (DIFLUCAN®)
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                                   reserved.
   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


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                               reserved.
     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

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                                       reserved.
          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?




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                             reserved.
                    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.




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                                 reserved.
                 Sulfonamides
• Why is this an effective antibacterial agent?
  – Humans derive folic acids from our diet and
    convert them to THF.




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   Amantadine and Rimantadine
• Block uncoating of viral particles by
  neutralizing the pH within the lysosome.

• Effective in fighting influenza type A virus.




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                             reserved.
     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
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                                       reserved.
    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


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                                reserved.
Inhibition of Nucleic Acid Synthesis




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    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


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                               reserved.
    Inhibition of Nucleic Acid Synthesis
• Rifampin: binds to bacterial RNA polymerase (enzyme
  used in transcription).
   – used to fight Mycobacterium tuberculosis




                  ©2011 prasit83.blogspot.com. All rights
                              reserved.
     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

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                                       reserved.
    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.




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                            reserved.
CLINICAL CONSIDERATIONS




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     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
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             Spectrum of Action
• Spectrum of Action: the number of different kinds of
  pathogens a drug acts against.
   – Narrow Spectrum and Broad-Spectrum Drugs




                   ©2011 prasit83.blogspot.com. All rights
                               reserved.
          Thought Question
What is the use of broad spectrum antibiotics
not always desirable? (Hint: think of the role
of normal microbiota).




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                          reserved.
       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




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                                reserved.
              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




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            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.


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                                 reserved.
            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.




                      ©2011 prasit83.blogspot.com. All rights
                                  reserved.
              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?




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                                reserved.
• Examples of organisms that often require
  multiple antibiotic resistance include:
  – Staphylococcus
                                                    Vancomycin-resistant
                                                   Staphylococcus aureus

  – Enterococcus

  – Pseudomonas

  – Mycobacterium

  – Plasmodium
                   ©2011 prasit83.blogspot.com. All rights
                               reserved.
                                          Prasit Kandel
                                          Pharmacist




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            reserved.

				
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Description: Definition, classification, mechanism of action of antimicrobial drugs.