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Antimicrobial Drugs

Antimicrobial Drugs. History Some definitions Mechanisms of Action or Antibacterials Protein synthesis inhibitors Cell wall synthesis inhibitors Plasma membrane-injuring agents Nucleic acid inhibitors Metabolic/enzyme inhibitors Antifungals Antivirals Antiprotozoan drugs

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Antimicrobial Drugs

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  1. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

  2. 1928 – Fleming discovered penicillin, produced by Penicillium. • 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Figure 20.1

  3. Table 20.1

  4. Definitions • 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 • Bacteriostatic/ Modes of action that either kill or bacteriocidal inhibit growth • Spectrum of activity Range of effect within or between groups of microbes; narrow vs. broad-spectrum

  5. Table 20.2

  6. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action of Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

  7. The Action of Antimicrobial Drugs Figure 20.2

  8. Protein Synthesis Inhibitors Figure 20.4

  9. The Action of Antimicrobial Drugs Figure 20.2

  10. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Penicilins • Penicillins • Natural penicillins: G, V • Semisynthetic penicillins • “-cillin “ suffix • Carbapenems • Monobactam

  11. Penicillins Figure 20.6

  12. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis:Cephalosporins • Cephalosporins • 2nd, 3rd, and 4th generations more effective against gram-negatives Figure 20.9

  13. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Polypeptides • Polypeptide antibiotics • Bacitracin • Topical application • Against gram-positives • Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus (e.g. MRSA)

  14. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Anti-Mycobacterials • Antimycobacterium antibiotics • Isoniazid (INH) • Inhibits mycolic acid synthesis • Ethambutol • Inhibits incorporation of mycolic acid

  15. The Action of Antimicrobial Drugs Figure 20.2

  16. Antibacterial Antibiotics Injury to the Plasma Membrane • Polymyxin B • Topical • Combined with bacitracin and neomycin in over-the-counter preparation

  17. The Action of Antimicrobial Drugs Figure 20.2

  18. Antibacterial Antibiotics Inhibitors of Nucleic Acid Synthesis • Rifamycin • Inhibits RNA synthesis by RNA polymerase • Antituberculosis • Quinolones and fluoroquinolones • Ciprofloxacin • Inhibits DNA gyrase so blocks DNA polymerase • Urinary tract infections

  19. The Action of Antimicrobial Drugs Figure 20.2

  20. Antibacterial Antibiotics Competitive Inhibitors • Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Figure 5.7

  21. TMZ - Trimethoprim + Sulfamethoxazole: Synergism Figure 20.13

  22. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

  23. Antifungal DrugsDamage through Ergosterol • Leakage thorough binding ergosterol • Amphotericin B • Inibitors of Ergosterol Syntehsis • Miconazole, fluconazole • Triazoles

  24. Antifungal DrugsInhibition of Cell Wall Synthesis • Echinocandins • Inhibit synthesis of -glucan • Cancidas is used against Candida and Pneumocystis

  25. Other Antifungal Drugs • Inhibition of Nucleic Acids • Flucytocine: cytosine analog interferes with RNA synthesis • Pentamidine isethionate for Pneumocytis : binds to DNA • Inhibition of Mitosis (microtubule beakers) • Griseofulvin • Used for superficial mycoses • Tolnaftate • Used for athlete's foot; action unknown

  26. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

  27. Antiviral DrugsNucleoside and Nucleotide Analogs Figure 20.16a

  28. Antiviral DrugsNucleoside and Nucleotide Analogs Figure 20.16b, c

  29. Antiviral DrugsEnzyme Inhibitors • Protease inhibitors • Indinavir • HIV • Inhibits attachment • Zanamivir • Influenza • Inhibits uncoating • Amantadine • Influenza • Interferons prevent spread of viruses to new cells • Viral hepatitis

  30. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

  31. Antiprotozoan Drugs • Chloroquine • Inhibits DNA synthesis • Malaria • Diiodohydroxyquin • Unknown • Amoeba • Metronidazole (Flagyl) • Damages DNA after becoming toxic from fermentation enzymes • Entamoeba, Trichomonas, Giardia (no mitochondria!) • (also works on obligately anaerobic bacteria like Clostrdium)

  32. Antihelminthic Drugs • Niclosamide • Prevents ATP generation • Tapeworms • Praziquantel • Alters membrane permeability • Flatworms • Pyantel pamoate • Neuromuscular block • Intestinal roundworms • Mebendazole • Inhibits nutrient absorption • Intestinal roundworms • Ivermectin • Paralyzes worm • Intestinal roundworms

  33. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance: Natural Selection

  34. Bacteria Populations Under Sub-Lethal Selection Pressure Evolve to Become More Resistant 1. Every bacterial population has variations in resistance due to gene transfer among them and mutation. Resistance is coded by DNA. 2. Some variants survive a brief antibiotic challenge because of their resistance. Population becomes increasingly resistant 3. Survivors are the “parents” of the next generation and pass on their particular resistance genes in their DNA. 4. The next and subsequent generations are composed of many variants. As a whole, the population is more resistant than the last.

  35. 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.

  36. 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

  37. Effects of Combinations of Drugs • Synergism occurs when the effect of two drugs together is greater than the effect of either alone. • E.g. Sulfamethoxazole and trimethoprim • Penicillin with beta-lactamase inhibitor (clav. acid) • Alcohol and sleeping pills • Antagonism occurs when the effect of two drugs together is less than the effect of either alone. • E.g. Ibuprofen (anti-diuretic properties) + diuretic • Penicillin + streptomycin

  38. 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

  39. Antimicrobial Drugs • History • Some definitions • Mechanisms of Action or Antibacterials • Protein synthesis inhibitors • Cell wall synthesis inhibitors • Plasma membrane-injuring agents • Nucleic acid inhibitors • Metabolic/enzyme inhibitors • Antifungals • Antivirals • Antiprotozoan drugs • Antihelminthics • Antibiotic Resistance

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