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 ChemotherapyThe use of drugs to treat a disease Antimicrobial drugsInterfere with the growth of microbes within a host AntibioticSubstance produced by a microbe that, in small amounts, inhibits another microbe Selective toxicityA drug that kills harmful microbes without damaging the host Bacteriostatic/Modes of action that either kill or bacteriocidalinhibit growth Spectrum of activityRange 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. Penicillins Natural penicillins: G, V Semisynthetic penicillins “-cillin “ suffix Carbapenems Monobactam Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis: Penicilins

11. Penicillins Figure 20.6

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

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

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

15. The Action of Antimicrobial Drugs Figure 20.2

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

17. The Action of Antimicrobial Drugs Figure 20.2

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

19. The Action of Antimicrobial Drugs Figure 20.2

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

21. Figure 20.13 TMZ - Trimethoprim + Sulfamethoxazole: Synergism

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. Leakage thorough binding ergosterol Amphotericin B Inibitors of Ergosterol Syntehsis Miconazole, fluconazole Triazoles Antifungal Drugs Damage through Ergosterol

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

25. 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 Other Antifungal Drugs

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 Drugs Nucleoside and Nucleotide Analogs Figure 20.16a

28. Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16b, c

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

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. 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) Antiprotozoan Drugs

32. 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 Antihelminthic Drugs

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 Population becomes increasingly 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. 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. 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 Resistance

36. 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 Antibiotic Resistance

37. 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 Effects of Combinations of Drugs

38. 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 The Future of Chemotherapeutic Agents

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