Antimicrobial Drugs

1
Antimicrobial Drugs

• Chemotherapy The use of drugs to treat a
  disease
• Antimicrobial drugs Interfere with the growth of
  microbes within a host
• Antibiotic Substance produced by a microbe
  that, in small amounts, inhibits another
  microbe
• Selective toxicity A drug that kills harmful
  microbes without damaging the host

2

• 1928 Fleming discovered penicillin, produced
  by Penicillium.
• 1940 Howard Florey and Ernst Chain performed
  first clinical trials of penicillin.
• All three were awarded the Nobel Prize in
  Medicine in 1945

Figure 20.1
3
Many Antibiotics come from Bacterial or Fungal
Sources
Table 20.1
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Table 20.2
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The Action of Antimicrobial Drugs

• Disrupt Cell Wall synthesis or through damage
• Disrupt Proteins synthesis
• Disrupt Nucleic Acid synthesis or function
• Disrupts essential metabolic enzymes-usually by
  competitive inhibition.

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The Action of Antimicrobial Drugs
Figure 20.2
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The Action of Antimicrobial Drugs
Figure 20.4
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Penicillins
Figure 20.6
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Penicillinase Enzyme Allows Bacteria to be
Resistant to Penicillin
Figure 20.8
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Other Inhibitors of Cell Wall Synthesis

• Cephlosporins-used Penicillin structure to
  synthesize antibiotics more effective on Gram
  Negative bacteria
• Polypeptide antibiotics
• Bacitracin
• Topical application
• Against gram-positives
• Vancomycin
• Glycopeptide
• Important "last line" against antibiotic
  resistant S. aureus

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Other Inhibitors of Cell Wall Synthesis

• Antimycobacterium antibiotics (TB, Leprosy)
• Isoniazid (INH)
• Inhibits mycolic acid synthesis
• Ethambutol
• Inhibits incorporation of mycolic acid

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Inhibitors of Protein Synthesis

• Chloramphenicol
• Broad spectrum
• Binds 50S subunit, inhibits peptide bond
  formation
• Aminoglycosides
• Streptomycin, neomycin, gentamycin
• Broad spectrum
• Changes shape of 30S subunit

13
Inhibitors of Protein Synthesis

• Tetracyclines
• Broad spectrum
• Interferes with tRNA attachment
• Erythromycin
• Gram-positives
• Binds 50S, prevents translocation

Injury to the Plasma Membrane

• Polymyxin B
• Topical
• Combined with bacitracin and neomycin in
  over-the-counter preparation

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Inhibitors of Nucleic Acid Synthesis

• Rifamycin
• Inhibits RNA synthesis
• Antituberculosis
• Quinolones and fluoroquinolones
• Ciprofloxacin
• Inhibits DNA gyrase
• Urinary tract infections

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Competitive Inhibitors

• Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum

Figure 5.7
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Figure 20.13
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Antifungal DrugsInhibition of Ergosterol
Synthesis

• Ergosterol important part of fungal cell wall.
  Unique to fungi, therefore a good drug target

Inhibition of Cell Wall Synthesis

• Echinocandins
• Inhibit synthesis of ?-glucan

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Antifungal DrugsInhibition of Nucleic Acids

• Flucytocine
• Cytosine analog interferes with RNA synthesis

Antifungal DrugsInhibition of Microtubules
(Mitosis)

• Tolnaftate
• Used for athlete's foot action unknown

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Antiviral DrugsNucleoside and Nucleotide Analogs
Figure 20.16a
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Antiviral DrugsNucleoside and Nucleotide Analogs
Figure 20.16b, c
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Antiviral Drugs Enzyme Inhibitors

• Protease inhibitors
• Indinavir
• HIV
• Inhibit attachment
• Zanamivir
• Influenza

Antiprotozoan Drugs

• Chloroquine
• Inhibits DNA synthesis
• Malaria

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Antibiotic Resistance

• A variety of mutations can lead to antibiotic
  resistance.
• Mechanisms of antibiotic resistance
• 1. Enzymatic destruction of drug
• 2. Prevention of penetration of drug
• 3. Alteration of drug's target site
• 4. Rapid ejection of the drug
• Resistance genes are often on plasmids or
  transposons that can be transferred between
  bacteria.

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Antibiotic Resistance

• Misuse of antibiotics selects for resistance
  mutants. Misuse includes
• Using outdated, weakened antibiotics
• Using antibiotics for the common cold and other
  inappropriate conditions
• Use of antibiotics in animal feed
• Failure to complete the prescribed regimen
• Using someone else's leftover prescription

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Disk-Diffusion Test
Figure 20.17
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Chemical Methods of Microbial Control

• Evaluating a disinfectant
• Disk-diffusion method

Figure 7.6
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• MIC Minimal inhibitory concentration
• MBC Minimal bactericidal concentration

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E Test
Figure 20.18
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Effects of Combinations of Drugs

• Synergism occurs when the effect of two drugs
  together is greater than the effect of either
  alone.
• Antagonism occurs when the effect of two drugs
  together is less than the effect of either alone.

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Effects of Combinations of Drugs
Figure 20.22
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The Future of Chemotherapeutic Agents

• Antimicrobial peptides
• Broad spectrum antibiotics from plants and
  animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)
• Antisense agents
• Complementary DNA or peptide nucleic acids that
  binds to a pathogen's virulence gene(s) and
  prevents transcription