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Antimicrobial Drugs. 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

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antimicrobial drugs1
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
historical perspective
Historical Perspective
  • Treatment hopeless before 1935
  • Paul Ehrlich, early 20th century
    • Father of chemotherapy
  • Fleming -- 1929
    • Penicillin discovered -- gram positives
  • Florey -- 1940
    • Penicillin -- first therapeutic use
  • Waksman -- 1944
    • Streptomycin -- gram negatives
  • 1947 -- Chloramphenicol -- broad spectrum
  • 1947 - present -- many
slide4
1928 – Fleming discovered penicillin, produced by Penicillium.
  • 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin.

Figure 20.1

properties of an ideal antibiotic
Properties of an ideal antibiotic
  • broad spectrum
  • stable--long shelf life
  • soluble in body fluids
  • stable toxicity
  • Nonallergenic
  • reasonable cost
  • selectively toxic
  • not likely to induce bacterial resistance
major genera that produce clinically useful antibiotics
Major genera that produce clinically useful antibiotics
  • Bacillus
  • Streptomyces
  • Cephalosporium
  • Penicillium
major targets of antimicrobial activity
Major targets of antimicrobial activity
  • Cell wall synthesis
    • penicillins, cephalosporins (beta-lactamase producing bacteria resistant to both, require active cell wall synthesis in actively growing cultures), bacitracin
  • Cell membrane function
    • amphotericin B (no growth requirement, changes membrane permeability by binding to sterols in fungal membranes, more side effects since membranes similar in all cells)
  • Protein synthesis
    • Aminoglycides, tetracyclines, chloramphenicol
major targets of antimicrobial activity1
Major targets of antimicrobial activity
  • DNA synthesisTranslation (mRNA--> protein):
    • Transcription: rifampin (TB), actinomycin D
      • Block movement of ribosome along mRNA: streptomycin, tetracycline
      • Prevent peptide bond formation by binding to ribosome: chloramphenicol, erythromycin
  • Antimetabolites (structural analogs of natural substances important in metabolism): PASA, sulfa drugs, INH
    • PASA very similar in structure to PABA, required by bacteria (but not human cells) for synthesis of folic acid
    • When PASA is used in synthesis of folic acid, results in nonfuctional folic acid analog and bacterial cell dies
antibacterial antibiotics inhibitors of cell wall synthesis
Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis
  • Penicillin
    • Natural penicillins
    • Semisynthetic penicillins
      • Penicilinase-resistant penicillins
      • Extended-spectrum penicillins
      • Penicillins + -lactamase inhibitors
      • Carbapenems
      • Monobactam
antibacterial antibiotics inhibitors of cell wall synthesis1
Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis
  • Cephalosporins
    • 2nd, 3rd, and 4th generations more effective against gram-negatives
  • Polypeptide antibiotics
    • Bacitracin
      • Topical application
      • Against gram-positives
    • Vancomycin
      • Glycopeptide
      • Important "last line" against antibiotic resistant S. aureus
antibacterial antibiotics inhibitors of protein synthesis
Antibacterial Antibiotics 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
antibacterial antibiotics inhibitors of protein synthesis1
Antibacterial Antibiotics Inhibitors of Protein Synthesis
  • Tetracyclines
    • Broad spectrum
      • Interferes with tRNA attachment
  • Macrolides
    • Gram-positives
      • Binds 50S, prevents translocation
  • Erythromycin
    • Gram-positives
      • Binds 50S, prevents translocation
definitions
MIC Minimal inhibitory concentration

MBC Minimal bactericidal concentration

Definitions
antibiotic resistance
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.
antibiotic resistance1
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
effects of combinations of drugs
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.
the future of chemotherapeutic agents
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