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Antibiotics lecture may 2010


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  • 1. Antimicrobial Drugs Fading Miracle? BLS 206 Lecture Hoza, A . S
  • 2. Ehrlich’s Magic Bullets• 1906: PaulEhrlich discoveredSalvarsan 606• 1930s: sulfa drugsdiscovered
  • 3. Fleming and Penicillin
  • 5. Terminologies Chemotherapy• The use of drugs to treat a disease• Selective toxicity: – A drug that kills harmful microbes without damaging the host
  • 6. TerminologiesAntibacterial spectrumRange of activity of an antibioticA broad spectrumAntibiotic that can inhibit wide range of G- positive and G-negative bacteria e.g. Carbapenems, 3-4th generationcephalosporins, quinolonesA narrow spectrumAntibiotic that is active only against a limited number ofbacteria e.g. penicillin G, 1-2nd generation cephalosporins,oxazolidone
  • 7. Bacteriostatic activity Level of antimicrobial activity that inhibits the growth of bacteriaMinimum inhibitory concentration (MIC) The lowest concentration that inhibits the growth of bacterial populationBactericidal activity Minimum bactericidal concentration (MBC) The lowest concentration that kills 99.9% of the bacterial population
  • 8. Antibiotic combinationsAntibiotic synergism Combination of antibiotics have enhanced activity when tested together compared with each antibiotic alone (e.g. 2 + 2 = 6) e.g. ampicillin+gentamicin in entercoccal carditisAdditive effect Combination of antibiotics has an additive effect (e.g. 2 + 2 = 4) e.g. combination of two ß-lactam antibioticsAntibiotic antagonism Combination in which the activity of one antibiotic interferes with the activity of the other (e.g. 2 + 2 < 4)
  • 9. Effects of Combinations of Drugs• Synergism occurs when the effect of two drugstogether is greater than the effect of either alone.• Antagonism occurs when the effect of two drugstogether is less than the effect of either alone.
  • 10. Effects of Combinations of Drugs
  • 11. Combined antibacterial therapy
  • 12. Antibiotic/Antimicrobial• Antibiotic: – Chemical produced by a microorganism that kills or inhibits the growth of another microorganism• Antimicrobial agent: – Chemical that kills or inhibits the growth of microorganisms
  • 13. Antimicrobial Agents• Disinfectant: •antimicrobial agent used only on inanimate objects• Chemotherapeutic agent: •antimicrobial agent that can be used internally• Bactericidal: •agent that kills bacteria• Bacteriostatic: •agent that inhibits the growth of bacteria
  • 14. MicrobialSources ofAntibiotics
  • 15. Antibiotic Spectrum of Activity• No antibiotic is effective against all microbes
  • 16. Mechanisms of Antimicrobial Action• Bacteria have their own enzymes for – Cell wall formation – Protein synthesis – DNA replication – RNA synthesis – Synthesis of essential metabolites
  • 17. Mechanisms of Antimicrobial Action• Viruses use host enzymes inside host cells• Fungi and protozoa have own eukaryotic enzymes• The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have
  • 18. Modes of Antimicrobial Action
  • 19. Basic mechanisms of antibiotics
  • 20. Basic mechanisms of antibiotic action (1) Disruption of bacterial cell wall ß-lactam antibiotics Penicillins, cephalosporins and cephamycins, carbapenems and monobactams, ß-lactamase inhibitor/ß- lactam combinationsGlycopeptides  VancomycinPolypeptides Bacitracin, polymyxinsDrugs used for treatment of mycobacterial infections Isoniazid, ethinamide, ethambutol, cycloserine
  • 21. Bacterial cell wall of G+ (A) and G- (B) bacteria
  • 22. Gram-positive and Gram-negative bacteria
  • 23. 2. Inhibition of protein synthesisActing at 30S ribosomes Aminoglycosides TetracyclinesActing at 50S ribosomes Chloramphenicol Macrolides Clindamycin Streptogramins Oxazolidones
  • 24. 3. Inhibition of nucleic acid synthesisActing on DNA replication Quinolones MetronidazoleActing on RNA synthesis Rifampin Rifabutin
  • 25. 4. AntimetabolitesSulfonamidesDapsoneTrimethoprimParaaminosalicylic acid
  • 26. Antimicrobial Agents
  • 27. Antimicrobial Agents
  • 28. Antimicrobial Agents
  • 29. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis• Penicillin (over 50 compounds) – Share 4-sided ring (ß lactam ring)• Natural penicillins • Narrow range of action • Susceptible to penicillinase (ß lactamase)
  • 30. Prokaryotic Cell WallsGram positive cell Gram negative cell wall wall
  • 31. Penicillins Figure 20.6
  • 32. Penicillinase (b Lactamase) Figure 20.8
  • 33. Semisynthetic Penicillins• Penicilinase- resistant penicillins • Carbapenems: very broad spectrum • Monobactam: Gram negative• Extended- spectrum penicillins• Penicillins + b-lactamase inhibitors
  • 34. Other Inhibitors of Cell Wall Synthesis• Cephalosporins – 2nd, 3rd, and 4th generations more effective against gram-negatives Figure 20.9
  • 35. Other Inhibitors of Cell Wall Synthesis• Polypeptide antibiotics – Bacitracin • Topical application • Against gram-positives – Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus
  • 36. Other Inhibitors of Cell Wall Synthesis• Antibiotics effective against Mycobacteria: – interfere with mycolic acid synthesis or incorporation – Isoniazid (INH) – Ethambutol
  • 37. Inhibitors of Protein Synthesis• Broad spectrum, toxicity problems• Examples – Chloramphenicol (bone marrow) – Aminoglycosides: Streptomycin, neomycin, gentamycin (hearing, kidneys) – Tetracyclines (Rickettsias & Chlamydia; GI tract) – Macrolides: Erythromycin (gram +, used in children)
  • 38. Injury to the Plasma Membrane• Polymyxin B (Gram negatives) – Topical – Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
  • 39. Inhibitors of Nucleic Acid Synthesis• Rifamycin – Inhibits RNA synthesis – Antituberculosis• Quinolones and fluoroquinolones – Ciprofloxacin – Inhibits DNA gyrase – Urinary tract infections
  • 40. Competitive Inhibitors– Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Figure 5.7
  • 41. Antifungal Drugs • Fungi are eukaryotes • Have unique sterols in their cell walls • Pathogenic fungi are often outside the body
  • 42. Antiviral Drugs• Viruses are composed of nucleic acid, protein capsid, and host membrane containing virus proteins• Viruses live inside host cells and use many host enzymes• Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly Figure 20.16a
  • 43. Antiviral DrugsNucleoside and Nucleotide Analogs Figure 20.16a
  • 44. Analogs Block DNA Synthesis Figure 20.16b, c
  • 45. Antiviral Drugs Enzyme Inhibitors• Inhibit assembly – Indinavir (HIV)• Inhibit attachment – Zanamivir (Influenza)• Inhibit uncoating – Amantadine (Influenza)
  • 46. Antiviral Drugs Enzyme Inhibitors• Interferons – prevent spread of viruses to new cells (Viral hepatitis)• Natural products of the immune system in viral infections
  • 47. Antiprotozoan Drugs• Protozoa are eukaryotic cells• Many drugs are experimental and their mode of action is unknown
  • 48. Antihelminthic Drugs • Helminths are macroscopic multicellular eukaryotic organisms: – tapeworms, – roundworms, – pinworms, – hookworms
  • 49. Antihelminthic Drugs• Prevent ATP generation (Tapeworms)• Alters membrane permeability (Flatworms)• Neuromuscular block (Intestinal roundworms)• Inhibits nutrient absorption (Intestinal roundworms)• Paralyzes worm (Intestinal roundworms)
  • 50. Measuring Antimicrobial Sensitivity• E Test• MIC: Minimal inhibitory concentration
  • 51. Measuring Antimicrobial Sensitivity: Disk Diffusion
  • 52. Penicillin