Antimicrobial Drugs

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Antimicrobial Drugs
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How were antimicrobial drugs first discovered?

• Alexander Fleming
• 1928
• S. aureus,
• Penicillium notatum
• Mass production 1940s
• Antibiosis
• Lead to antibiotic
• Different from chemotherapy!

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Where do antibiotics come from?

• From other bacteria found in
• Soil
• Bacteria
• Streptomyces more than half!
• Bacillus
• Molds
• Penicillium
• Cephalosporium

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What is an antibiotics spectrum?

• Number/types of organisms it affects
• Narrow spectrum of antibiotic activity
• Penicillin G mostly only gram
• Broad spectrum antibiotic activity
• Tetracycline
• Pros vs cons
• Lead to
  superinfections

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How do antimicrobial drugs work?

• Depends on the drug
• Bactericidal or bacteristatic
• Modes of action include
• Cell wall destruction
• Inhibiting transcription or translation
• Plasma membrane damage
• Inhibiting DNA synthesis
• Inhibiting synthesis of metabolites

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How can an antibiotic destroy the cell wall?

• Penicillin and others
• Prevent synthesis (crosslinking)
• Cell then lyses due to weakened wall
• Only affects actively growing cells
• Does not affect humans

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Can you discuss some examples?

• Penicillin
• Penicillin G
• Narrow spectrum, penicillinase susceptible
• Penicillinase-resistant penicillins
• Methicillin
• MRSA
• Replacing methicillin oxacillin, nafcillin
• Extended spectrum penicillins
• Ampicillin, amoxicillin
• Effective against both gram and
• Cephalosporins
• Penicillinase resistant, gram effective
• Vancomycin
• Narrow spectrum
• Last resort

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How can they inhibit protein synthesis?

• Tetracyclines, chloramphenicol, streptomycin,
  etc.

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How do they injure the PM?

• Polypeptide antibiotics (e.g. polymyxin B)
• Change permeability of PM

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How do they inhibit DNA synthesis?

• Limited usefulness WHY?
• Quinolones
• Inhibits DNA gyrase
• UTIs
• Fluoroquinolones
• Ciprofloxacin (Cipro)
• Affects cartilage development
• Can be used in adults

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How do they inhibit synthesis of important
metabolites?

• Competitive inhibition
• Synthetic drug
• Sulfaniamide inhibits para-aminobenzoic acid
  (PABA)
• PABA is precursor for making folic acid
• Sulfa prevents conversion
• Humans dont make folic acid, we eat it!
• Broad spectrum

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What are some antifungal drugs?

• Many target fungal sterols
• Ergosterol vs. (humans) cholesterol
• Azoles
• Athletes foot, yeast infection treatment
• Others target chitin cell wall
• Echinocandins
• Many others which we wont worry about

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What about antiviral drugs?

• Very few WHY????
• Drugs can attack
• Attachment
• Penetration
• Uncoating
• DNA/RNA synthesis
• Virion assembly

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Can you tell me about a couple?

• Nucleosides and nucleotide analogs
• Acyclovir genital herpes
• Interferons

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What tests are used to identify antimicrobial
activity?

• Disk-diffusion
• Cant determine bactericidal vs. stasis
• Gradient diffusion
• Broth dilution
• Can determine bactericidal vs. -stasis

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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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Whats next?
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Is there a downside to antimicrobial or
antibiotic use?

• Yes!
• Natural selection
• Antibiotics
• Always take the full prescription
• They dont work on viruses!

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What types of resistance are there?

• video
• Destruction of the drug (e.g. penicillinase)
• Prevention of drug penetration
• Common with tetracycline
• Alteration of drug target site
• Rapid efflux
• Heredity
• Transformation, transduction, transposons

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Resistance to Antibiotics
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Future of Chemotherapeutic Agents

• Antimicrobial peptides
• Broad-spectrum antibiotics
• Nisin (lactic acid bacteria)
• Magainin (frogs)
• Cecropin (moths)
• Antisense agents
• Complementary DNA that binds
• a pathogen's virulence gene(s)
• and prevents transcription
• Fomivirsen to treat CMV retinitis
• siRNA
• Complementary RNA that binds mRNA to inhibit
  translation