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					Antimicrobial Drugs

   Fading Miracle?
Ehrlich’s Magic Bullets
Fleming and Penicillin
         Chemotherapy
• The use of drugs to treat a disease

• Selective toxicity: A drug that kills
  harmful microbes without damaging
  the host
   Antibiotic/Antimicrobial
• Antibiotic: Chemical produced
  by a microorganism that kills or
  inhibits the growth of another
  microorganism
• Antimicrobial agent: Chemical
  that kills or inhibits the growth of
  microorganisms
Microbial
 Sources
    of
Antibiotics
Antibiotic Spectrum of Activity




• No antibiotic is effective against all
  microbes
       Mechanisms of
     Antimicrobial Action
• Bacteria have their own enzymes
  for
   –Cell wall formation
   –Protein synthesis
   –DNA replication
   –RNA synthesis
   –Synthesis of essential
    metabolites
       Mechanisms of
     Antimicrobial Action
• Viruses use host enzymes inside
  host cells
• Fungi and protozoa have own
  eukaryotic enzymes

• The more similar the pathogen and
  host enzymes, the more side
  effects the antimicrobials will have
Modes of Antimicrobial Action
    Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
• Penicillin (over 50 compounds)
  –Share 4-sided ring (b lactam ring)
• Natural penicillins
    • Narrow range of action
    • Susceptible to penicillinase (b
      lactamase)
Prokaryotic Cell Walls
Penicillins
  Fig 20.6




              Figure 20.6
Penicillinase (b Lactamase)




                              Figure 20.8
   Semisynthetic Penicillins

• Penicilinase-resistant penicillins
    • Carbapenems: very broad
      spectrum
    • Monobactam: Gram negative
• Extended-spectrum penicillins
• Penicillins + b-lactamase inhibitors
   Other Inhibitors of Cell Wall
            Synthesis
• Cephalosporins
  –2nd, 3rd, and
   4th
   generations
   more effective
   against gram-
   negatives
                                   Figure 20.9
    Other Inhibitors of Cell Wall
             Synthesis
• Polypeptide antibiotics
  –Bacitracin
    • Topical application
    • Against gram-positives
  –Vancomycin
    • Glycopeptide
    • Important "last line" against
      antibiotic resistant S. aureus
  Other Inhibitors of Cell Wall
           Synthesis
• Antibiotics
  effective against
  Mycobacteria:
  interfere with
  mycolic acid
  synthesis or
  incorporation
   – Isoniazid (INH)
   – Ethambutol
  Inhibitors of Protein Synthesis
• Broad spectrum, toxicity problems
• Examples
  – Chloramphenicol (bone marrow)
  – Aminoglycosides: Streptomycin,
    neomycin, gentamycin (hearing, kidneys)
  – Tetracyclines (Rickettsias & Chlamydia;
    GI tract)
  – Macrolides: Erythromycin (gram +, used
    in children)
 Injury to the Plasma Membrane

• Polymyxin B (Gram negatives)
  –Topical
  –Combined with bacitracin and
   neomycin (broad spectrum) in over-
   the-counter preparation
     Inhibitors of Nucleic Acid
             Synthesis
• Rifamycin
  –Inhibits RNA synthesis
  –Antituberculosis
• Quinolones and fluoroquinolones
  –Ciprofloxacin
  –Inhibits DNA gyrase
  –Urinary tract infections
     Competitive Inhibitors
–Sulfonamides (Sulfa drugs)
 • Inhibit folic acid synthesis
 • Broad spectrum




                                  Figure 5.7
Antifungal Drugs
        • Fungi are
          eukaryotes
        • Have unique
          sterols in their cell
          walls
        • Pathogenic fungi
          are often outside
          the body
         Antiviral Drugs
• Viruses are composed of nucleic
  acid, protein capsid, and host
  membrane containing virus proteins
• Viruses live inside host cells and
  use many host enzymes
• Some viruses have unique
  enzymes for DNA/RNA synthesis or
  protein cutting in virus assembly
                                  Figure 20.16a
        Antiviral Drugs
Nucleoside and Nucleotide Analogs




                                Figure 20.16a
Analogs Block DNA Synthesis




                         Figure 20.16b, c
       Antiviral Drugs
      Enzyme Inhibitors
• Inhibit assembly
   –Indinavir (HIV)
• Inhibit attachment
   –Zanamivir (Influenza)
• Inhibit uncoating
   –Amantadine (Influenza)
         Antiviral Drugs
        Enzyme Inhibitors

• Interferons prevent spread of viruses
  to new cells (Viral hepatitis)
• Natural products of the immune
  system in viral infections
      Antiprotozoan Drugs


• Protozoa are
  eukaryotic cells
• Many drugs are
  experimental and
  their mode of
  action is unknown
Antihelminthic Drugs
          • Helminths are
            macroscopic
            multicellular
            eukaryotic
            organisms:
            tapeworms,
            roundworms,
            pinworms,
            hookworms
        Antihelminthic Drugs
• Prevent ATP generation (Tapeworms)
• Alters membrane permeability
  (Flatworms)
• Neuromuscular block (Intestinal
  roundworms)
• Inhibits nutrient absorption (Intestinal
  roundworms)
• Paralyzes worm (Intestinal
  roundworms)
      Measuring Antimicrobial
           Sensitivity

• E Test
• MIC: Minimal
  inhibitory
  concentration
Measuring Antimicrobial
Sensitivity: Disk Diffusion
Antibiotic Resistance




                        Figure 20.20
  Antimicrobial Resistance

• Relative or complete lack of
  effect of antimicrobial against a
  previously susceptible microbe
• Increase in MIC
   Mechanisms of Antibiotic
        Resistance

• Enzymatic destruction of drug
• Prevention of penetration of drug
• Alteration of drug's target site
• Rapid ejection of the drug
Antibiotic Selection for
 Resistant Bacteria
  What Factors Promote
 Antimicrobial Resistance?

• Exposure to sub-optimal levels
  of antimicrobial
• Exposure to microbes carrying
  resistance genes
Inappropriate Antimicrobial
           Use
• Prescription not taken correctly
• Antibiotics for viral infections
• Antibiotics sold without medical
  supervision
• Spread of resistant microbes in
  hospitals due to lack of hygiene
Inappropriate Antimicrobial
           Use
• Lack of quality control in
  manufacture or outdated
  antimicrobial
• Inadequate surveillance or
  defective susceptibility assays
• Poverty or war
• Use of antibiotics in foods
     Antibiotics in Foods
• Antibiotics are used in animal feeds
  and sprayed on plants to prevent
  infection and promote growth
• Multi drug-resistant Salmonella
  typhi has been found in 4 states in
  18 people who ate beef fed
  antibiotics
   Consequences of
Antimicrobial Resistance
            • Infections
              resistant to
              available
              antibiotics
            • Increased
              cost of
              treatment
Multi-Drug Resistant TB
      MRSA “mer-sah”
• Methicillin-Resistant
  Staphylococcus aureus
• Most frequent nosocomial
  (hospital-acquired) pathogen
• Usually resistant to several
  other antibiotics
Vancomycin Resistant Enterococci
Vancomycin Use USA
   Proposals to Combat
  Antimicrobial Resistance

• Speed development of new
  antibiotics
• Track resistance data nationwide
• Restrict antimicrobial use
• Direct observed dosing (TB)
   Proposals to Combat
  Antimicrobial Resistance
• Use more narrow spectrum
  antibiotics
• Use antimicrobial cocktails
     The Future of
 Chemotherapeutic Agents
• Antimicrobial peptides
  –Broad spectrum antibiotics from
   plants and animals
    • Squalamine (sharks)
    • Protegrin (pigs)
    • Magainin (frogs)
        The Future of
    Chemotherapeutic Agents

• Antisense agents
  –Complementary DNA or peptide
   nucleic acids that binds to a
   pathogen's virulence gene(s) and
   prevents transcription

				
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