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Antimicrobial Drugs  Fading Miracle? BLS 206 Lecture   Hoza, A . S
Ehrlich’s Magic Bullets• 1906: PaulEhrlich discoveredSalvarsan 606• 1930s: sulfa drugsdiscovered
Fleming and Penicillin
TERMINOLOGIES
Terminologies             Chemotherapy• The use of drugs to treat a disease• Selective toxicity:  – A drug that kills harm...
TerminologiesAntibacterial spectrumRange of activity of an antibioticA broad spectrumAntibiotic that can inhibit wide r...
Bacteriostatic activity  Level of antimicrobial activity that inhibits the  growth of bacteriaMinimum inhibitory concen...
Antibiotic combinationsAntibiotic synergism  Combination of antibiotics have enhanced activity     when tested together ...
Effects of Combinations of Drugs• Synergism occurs when the effect of two drugstogether is greater than the effect of eith...
Effects of Combinations of Drugs
Combined antibacterial therapy
Antibiotic/Antimicrobial• Antibiotic:  – Chemical produced by a microorganism that    kills or inhibits the growth of anot...
Antimicrobial Agents• Disinfectant:   •antimicrobial agent used only on inanimate   objects• Chemotherapeutic agent:   •an...
MicrobialSources ofAntibiotics
Antibiotic Spectrum of Activity• No antibiotic is effective against all microbes
Mechanisms of Antimicrobial Action• Bacteria have their own enzymes for  – Cell wall formation  – Protein synthesis  – DNA...
Mechanisms of Antimicrobial Action• Viruses use host enzymes inside host cells• Fungi and protozoa have own eukaryotic enz...
Modes of Antimicrobial Action
Basic mechanisms of antibiotics
Basic mechanisms of antibiotic action             (1) Disruption of bacterial cell wall ß-lactam antibiotics   Penicilli...
Bacterial cell wall of G+ (A) and G- (B) bacteria
Gram-positive and Gram-negative bacteria
2. Inhibition of protein synthesisActing at 30S ribosomes  Aminoglycosides  TetracyclinesActing at 50S ribosomes  Chl...
3. Inhibition of nucleic acid synthesisActing on DNA replication  Quinolones  MetronidazoleActing on RNA synthesis  R...
4. AntimetabolitesSulfonamidesDapsoneTrimethoprimParaaminosalicylic acid
Antimicrobial Agents
Antimicrobial Agents
Antimicrobial Agents
Antibacterial Antibiotics Inhibitors of Cell Wall                      Synthesis• Penicillin (over 50 compounds)  – Share ...
Prokaryotic Cell WallsGram positive cell       Gram negative cell      wall                     wall
Penicillins              Figure 20.6
Penicillinase (b Lactamase)                              Figure 20.8
Semisynthetic Penicillins• Penicilinase- resistant penicillins    • Carbapenems: very broad spectrum    • Monobactam: Gram...
Other Inhibitors of Cell Wall Synthesis• Cephalosporins  – 2nd, 3rd, and 4th    generations more    effective against    g...
Other Inhibitors of Cell Wall Synthesis• Polypeptide antibiotics  – Bacitracin     • Topical application     • Against gra...
Other Inhibitors of Cell Wall Synthesis• Antibiotics effective against  Mycobacteria:   – interfere with mycolic acid     ...
Inhibitors of Protein Synthesis• Broad spectrum, toxicity problems• Examples  – Chloramphenicol (bone marrow)  – Aminoglyc...
Injury to the Plasma Membrane• Polymyxin B (Gram negatives)  – Topical  – Combined with bacitracin and neomycin    (broad ...
Inhibitors of Nucleic Acid Synthesis• Rifamycin  – Inhibits RNA synthesis  – Antituberculosis• Quinolones and fluoroquinol...
Competitive Inhibitors– Sulfonamides (Sulfa drugs)  • Inhibit folic acid synthesis  • Broad spectrum                      ...
Antifungal Drugs        • Fungi are eukaryotes        • Have unique sterols in          their cell walls        • Pathogen...
Antiviral Drugs• Viruses are composed of nucleic acid, protein  capsid, and host membrane containing virus proteins• Virus...
Antiviral DrugsNucleoside and Nucleotide Analogs                                    Figure 20.16a
Analogs Block DNA Synthesis                              Figure 20.16b, c
Antiviral Drugs Enzyme Inhibitors• Inhibit assembly  – Indinavir (HIV)• Inhibit attachment   – Zanamivir (Influenza)• Inhi...
Antiviral Drugs Enzyme Inhibitors• Interferons   – prevent spread of viruses to new cells (Viral     hepatitis)• Natural p...
Antiprotozoan Drugs• Protozoa are eukaryotic  cells• Many drugs are  experimental and their  mode of action is unknown
Antihelminthic Drugs          • Helminths are            macroscopic            multicellular eukaryotic            organi...
Antihelminthic Drugs• Prevent ATP generation (Tapeworms)• Alters membrane permeability (Flatworms)• Neuromuscular block (I...
Measuring Antimicrobial Sensitivity• E Test• MIC: Minimal  inhibitory  concentration
Measuring Antimicrobial Sensitivity: Disk Diffusion
Penicillin
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Antibiotics lecture may 2010

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Transcript of "Antibiotics lecture may 2010"

  1. 1. Antimicrobial Drugs Fading Miracle? BLS 206 Lecture Hoza, A . S
  2. 2. Ehrlich’s Magic Bullets• 1906: PaulEhrlich discoveredSalvarsan 606• 1930s: sulfa drugsdiscovered
  3. 3. Fleming and Penicillin
  4. 4. TERMINOLOGIES
  5. 5. Terminologies Chemotherapy• The use of drugs to treat a disease• Selective toxicity: – A drug that kills harmful microbes without damaging the host
  6. 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. 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. 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. 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. 10. Effects of Combinations of Drugs
  11. 11. Combined antibacterial therapy
  12. 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. 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. 14. MicrobialSources ofAntibiotics
  15. 15. Antibiotic Spectrum of Activity• No antibiotic is effective against all microbes
  16. 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. 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. 18. Modes of Antimicrobial Action
  19. 19. Basic mechanisms of antibiotics
  20. 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. 21. Bacterial cell wall of G+ (A) and G- (B) bacteria
  22. 22. Gram-positive and Gram-negative bacteria
  23. 23. 2. Inhibition of protein synthesisActing at 30S ribosomes Aminoglycosides TetracyclinesActing at 50S ribosomes Chloramphenicol Macrolides Clindamycin Streptogramins Oxazolidones
  24. 24. 3. Inhibition of nucleic acid synthesisActing on DNA replication Quinolones MetronidazoleActing on RNA synthesis Rifampin Rifabutin
  25. 25. 4. AntimetabolitesSulfonamidesDapsoneTrimethoprimParaaminosalicylic acid
  26. 26. Antimicrobial Agents
  27. 27. Antimicrobial Agents
  28. 28. Antimicrobial Agents
  29. 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. 30. Prokaryotic Cell WallsGram positive cell Gram negative cell wall wall
  31. 31. Penicillins Figure 20.6
  32. 32. Penicillinase (b Lactamase) Figure 20.8
  33. 33. Semisynthetic Penicillins• Penicilinase- resistant penicillins • Carbapenems: very broad spectrum • Monobactam: Gram negative• Extended- spectrum penicillins• Penicillins + b-lactamase inhibitors
  34. 34. Other Inhibitors of Cell Wall Synthesis• Cephalosporins – 2nd, 3rd, and 4th generations more effective against gram-negatives Figure 20.9
  35. 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. 36. Other Inhibitors of Cell Wall Synthesis• Antibiotics effective against Mycobacteria: – interfere with mycolic acid synthesis or incorporation – Isoniazid (INH) – Ethambutol
  37. 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. 38. Injury to the Plasma Membrane• Polymyxin B (Gram negatives) – Topical – Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation
  39. 39. Inhibitors of Nucleic Acid Synthesis• Rifamycin – Inhibits RNA synthesis – Antituberculosis• Quinolones and fluoroquinolones – Ciprofloxacin – Inhibits DNA gyrase – Urinary tract infections
  40. 40. Competitive Inhibitors– Sulfonamides (Sulfa drugs) • Inhibit folic acid synthesis • Broad spectrum Figure 5.7
  41. 41. Antifungal Drugs • Fungi are eukaryotes • Have unique sterols in their cell walls • Pathogenic fungi are often outside the body
  42. 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. 43. Antiviral DrugsNucleoside and Nucleotide Analogs Figure 20.16a
  44. 44. Analogs Block DNA Synthesis Figure 20.16b, c
  45. 45. Antiviral Drugs Enzyme Inhibitors• Inhibit assembly – Indinavir (HIV)• Inhibit attachment – Zanamivir (Influenza)• Inhibit uncoating – Amantadine (Influenza)
  46. 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. 47. Antiprotozoan Drugs• Protozoa are eukaryotic cells• Many drugs are experimental and their mode of action is unknown
  48. 48. Antihelminthic Drugs • Helminths are macroscopic multicellular eukaryotic organisms: – tapeworms, – roundworms, – pinworms, – hookworms
  49. 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. 50. Measuring Antimicrobial Sensitivity• E Test• MIC: Minimal inhibitory concentration
  51. 51. Measuring Antimicrobial Sensitivity: Disk Diffusion
  52. 52. Penicillin
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