2. Antimicrobial Drugs Fading Miracle?

3. Ehrlich’s Magic Bullets

4. Fleming and Penicillin

5. Chemotherapy The use of drugs to treat a disease Selective toxicity: A drug that kills harmful microbes without damaging the host

6. 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

7. Microbial Sources of Antibiotics

8. Antibiotic Spectrum of Activity No antibiotic is effective against all microbes

9. Mechanisms of Antimicrobial Action Bacteria have their own enzymes for –Cell wall formation –Protein synthesis –DNA replication –RNA synthesis –Synthesis of essential metabolites

10. 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

11. Modes of Antimicrobial Action

12. Penicillin (over 50 compounds) –Share 4-sided ring (  lactam ring) Natural penicillins Narrow range of action Susceptible to penicillinase (  lactamase) Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

13. Prokaryotic Cell Walls

14. Penicillins Fig 20.6 Figure 20.6

15. Penicillinase (  Lactamase) Figure 20.8

16. Penicilinase-resistant penicillins Carbapenems: very broad spectrum Monobactam: Gram negative Extended-spectrum penicillins Penicillins +  -lactamase inhibitors Semisynthetic Penicillins

17. Cephalosporins –2 nd, 3 rd, and 4 th generations more effective against gram-negatives Other Inhibitors of Cell Wall Synthesis Figure 20.9

18. Polypeptide antibiotics –Bacitracin Topical application Against gram-positives –Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus Other Inhibitors of Cell Wall Synthesis

19. Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation –Isoniazid (INH) –Ethambutol

20. 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) Inhibitors of Protein Synthesis

21. Polymyxin B (Gram negatives) –Topical –Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation Injury to the Plasma Membrane

22. Rifamycin –Inhibits RNA synthesis –Antituberculosis Quinolones and fluoroquinolones –Ciprofloxacin –Inhibits DNA gyrase –Urinary tract infections Inhibitors of Nucleic Acid Synthesis

23. –Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Broad spectrum Competitive Inhibitors Figure 5.7

24. Antifungal Drugs Fungi are eukaryotes Have unique sterols in their cell walls Pathogenic fungi are often outside the body

25. 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

26. Antiviral Drugs Nucleoside and Nucleotide Analogs Figure 20.16a

27. Figure 20.16b, c Analogs Block DNA Synthesis

28. Inhibit assembly –Indinavir (HIV) Inhibit attachment –Zanamivir (Influenza) Inhibit uncoating –Amantadine (Influenza) Antiviral Drugs Enzyme Inhibitors

29. Interferons prevent spread of viruses to new cells (Viral hepatitis) Natural products of the immune system in viral infections Antiviral Drugs Enzyme Inhibitors

30. Antiprotozoan Drugs Protozoa are eukaryotic cells Many drugs are experimental and their mode of action is unknown

31. Antihelminthic Drugs Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms

32. Prevent ATP generation (Tapeworms) Alters membrane permeability (Flatworms) Neuromuscular block (Intestinal roundworms) Inhibits nutrient absorption (Intestinal roundworms) Paralyzes worm (Intestinal roundworms) Antihelminthic Drugs

33. Measuring Antimicrobial Sensitivity E Test MIC: Minimal inhibitory concentration

34. Measuring Antimicrobial Sensitivity: Disk Diffusion

35. Figure 20.20 Antibiotic Resistance

36. Antimicrobial Resistance Relative or complete lack of effect of antimicrobial against a previously susceptible microbe Increase in MIC

37. Enzymatic destruction of drug Prevention of penetration of drug Alteration of drug's target site Rapid ejection of the drug Mechanisms of Antibiotic Resistance

38. Antibiotic Selection for Resistant Bacteria

39. What Factors Promote Antimicrobial Resistance? Exposure to sub-optimal levels of antimicrobial Exposure to microbes carrying resistance genes

40. Inappropriate Antimicrobial Use Prescription not taken correctly Antibiotics for viral infections Antibiotics sold without medical supervision Spread of resistant microbes in hospitals due to lack of hygiene

41. Inappropriate Antimicrobial Use Lack of quality control in manufacture or outdated antimicrobial Inadequate surveillance or defective susceptibility assays Poverty or war Use of antibiotics in foods

42. Antibiotics in Foods Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics

43. Consequences of Antimicrobial Resistance Infections resistant to available antibiotics Increased cost of treatment

45. Multi-Drug Resistant TB

46. MRSA “mer-sah” Methicillin-Resistant Staphylococcus aureus Most frequent nosocomial (hospital- acquired) pathogen Usually resistant to several other antibiotics

47. Vancomycin Resistant Enterococci

48. Vancomycin Use USA

49. Proposals to Combat Antimicrobial Resistance Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use Direct observed dosing (TB)

50. Proposals to Combat Antimicrobial Resistance Use more narrow spectrum antibiotics Use antimicrobial cocktails

51. Antimicrobial peptides –Broad spectrum antibiotics from plants and animals Squalamine (sharks) Protegrin (pigs) Magainin (frogs) The Future of Chemotherapeutic Agents

52. 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