1. Plants and Fungi Used to Treat Infectious Disease

2. Infectious Disease World wide, infectious disease is the number one cause of death accounting for approximately one- half of all deaths in tropical countries Infectious disease mortality rates are actually increasing in developed countries, such as US Infectious disease underlying cause of death in 8% of deaths occurring in US

3. מונחים Antimicrobial = a substance which destroys or inhibits the growth of microorganisms Antiseptic = a substance that checks the growth or action of microorganisms especially in or on living tissue Antibiotic = a substance produced by or derived from a microorganism and able to inhibit or kill another microorganism

4. פניצילין תוצר לוואי של זני Penicillium מסויימים. מעכבים גידול של חיידקים גרם חיוביים. מונעים את הביוסינתזה של הפפטידוגליקן ולכן גורמים למות תא החיידק ע"י ליזיס.

5. גילוי הפניצילין במאה ה- 19 החוקרים הבאים צפו במיני Penicillium spp שמנעו גידול חיידקים : –Roberts - 1874 –Tyndall – 1881 –Others Flemming - 1928

6. Sir Alexander Fleming

7. צלחת הפטרי של פלמינג קורי הפטריה Penicillium notatum הרגו את התרבית של חיידקי Staphylococcus aureus

8. איזור העיכוב סביב מושבת הפטריה ישנו איזור שבו אין גידול חיידקים. איזור העיכוב – נובע מדיפוזיה של חומר בעל תכונות אנטיביוטיות מהפטריה.

10. Principles and Definitions Antibiotic susceptibility testing (in vitro) –Minimum inhibitory concentration (MIC) Lowest concentration that results in inhibition of visible growth –Minimum bactericidal concentration (MBC) Lowest concentration that kills 99.9% of the original inoculum

11. Antibiotic Susceptibility Testing 8 4021 Tetracycline (  g/ml) MIC = 2  g/ml Determination of MIC ChlAmp Ery Str Tet Disk Diffusion Test

12. Zone Diameter Standards for Disk Diffusion Tests

13. sites of antiobiotic action

14. אנטיביוטיקה המעכבת סינתזת חלבון

15. Review of Initiation of Protein Synthesis 30S 1 3 2 GTP 123 Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met-tRNA Spectinomycin Aminoglycosides 1 2 GDP + Pi 50S 70S Initiation Complex AP

16. Review of Elongation of Protein Synthesis GTP AP Tu GTP Tu GDP Ts Tu + GDP Ts Pi PA Tetracycline AP Erythromycin Fusidic AcidChloramphenicol G GTP G GDP + Pi G GDP AP + GTP

17. Protein Synthesis Microbe Library -American Society for Microbiology www.microbelibrary.org

18. Protein Synthesis Inhibitors עיכוב סינתזת חלבון Mostly bacteriostatic Selectivity due to differences in prokaryotic and eukaryotic ribosomes Some toxicity - eukaryotic 70S ribosomes

19. Antimicrobials that Bind to the 30S Ribosomal Subunit

20. Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. By binding to the 16 S r- RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. May also destabilize bacterial membranes.

21. Microbe Library American Society for Microbiology www.microbelibrary.org

22. Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) Spectrum of Activity -Many gram-negative and some gram-positive bacteria; Not useful for anaerobic (oxygen required for uptake of antibiotic) or intracellular bacteria. Resistance - Common Synergy - The aminoglycosides synergize with $ -lactam antibiotics. The $ -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.

23. Tetracyclines (bacteriostatic) tetracycline, minocycline and doxycycline Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. Spectrum of activity - Broad spectrum; Useful against intracellular bacteria Resistance - Common Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.

24. Spectinomycin (bacteriostatic) Mode of action - Spectinomycin reversibly interferes with m-RNA interaction with the 30S ribosome. It is structurally similar to the aminoglycosides but does not cause misreading of mRNA. Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae Resistance - Rare in Neisseria gonorrhoeae

25. Antimicrobials that Bind to the 50S Ribosomal Subunit

26. Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic) Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range Resistance - Common Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.

27. Macrolides (bacteriostatic) erythromycin, clarithromycin, azithromycin, spiramycin Mode of action - The macrolides inhibit translocation. Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella Resistance - Common

28. Microbe Library American Society for Microbiology www.microbelibrary.org

29. Antimicrobials that Interfere with Elongation Factors Selectivity due to differences in prokaryotic and eukaryotic elongation factors

30. Fusidic acid (bacteriostatic) Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex. Spectrum of activity - Gram-positive cocci

31. Inhibitors of Nucleic Acid Synthesis

32. Inhibitors of RNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic RNA polymerase

33. Rifampin, Rifamycin, Rifampicin, Rifabutin (bactericidal) Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis. Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis Resistance - Common Combination therapy - Since resistance is common, rifampin is usually used in combination therapy.

34. Inhibitors of DNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic enzymes

35. Quinolones (bactericidal) nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. Spectrum of activity - Gram-positive cocci and urinary tract infections Resistance - Common for nalidixic acid; developing for ciprofloxacin

36. Antimetabolite Antimicrobials

37. Inhibitors of Folic Acid Synthesis Basis of Selectivity Review of Folic Acid Metabolism p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine TrimethoprimSulfonamides

38. Sulfonamides, Sulfones (bacteriostatic) Mode of action - These antimicrobials are analogues of para- aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.

39. Trimethoprim, Methotrexate, Pyrimethamine (bacteriostatic) Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.

40. Anti-Mycobacterial Antibiotics

41. Para-aminosalicylic acid (PSA) (bacteriostatic) Mode of action - Similar to sulfonamides Spectrum of activity - Specific for Mycobacterium tuberculosis

42. Dapsone (bacteriostatic) Mode of action - Similar to sulfonamides Spectrum of activity - Used in treatment of leprosy (Mycobacterium leprae)

43. Isoniazid (INH) (bacteriostatic ) Mode of action - Isoniazid inhibits synthesis of mycolic acids. Spectrum of activity - Used in treatment of tuberculosis Resistance - Has developed

44. Antimicrobial Drug Resistance Principles and Definitions Clinical resistance vs actual resistance Resistance can arise by mutation or by gene transfer (e.g. acquisition of a plasmid) Resistance provides a selective advantage Resistance can result from single or multiple steps Cross resistance vs multiple resistance –Cross resistance -- Single mechanism-- closely related antibiotics –Multiple resistance -- Multiple mechanisms -- unrelated antibiotics

45. Antimicrobial Drug Resistance Mechanisms Altered permeability –Altered influx Gram negative bacteria

46. Microbe Library American Society for Microbiology www.microbelibrary.org

47. Antimicrobial Drug Resistance Mechanisms Altered permeability –Altered efflux tetracycline Microbe Library American Society for Microbiology www.microbelibrary.org

48. Antimicrobial Drug Resistance Mechanisms Inactivation –  -lactamase –Chloramphenicol acetyl transferase Microbe Library American Society for Microbiology www.microbelibrary.org

49. Antimicrobial Drug Resistance Mechanisms Altered target site –Penicillin binding proteins (penicillins) –RNA polymerase (rifampin) –30S ribosome (streptomycin) Microbe Library American Society for Microbiology www.microbelibrary.org

50. Antimicrobial Drug Resistance Mechanisms Replacement of a sensitive pathway –Acquisition of a resistant enzyme (sulfonamides, trimethoprim)

51. Beta-Lactam Structure

52.  Lactam Basic Structure

53. Penicillin-G

54. Penicillin-V phenoxy methyl penicillin

55. Semi-Synthetic Penicillins A strain of Penicillium chrysogenum found that produced large amounts of 6-amino penicillanic acid (6-APA) 6-APA lacked antibiotic activity but it could be used to add a variety of side chains and create semi-synthetic penicillins –methicillin and ampicillin Semi-synthetics have made penicillins a more versatile group of antibiotics

56. 6-APA Ampicillin Methycillin R=H

57. Resistance due to  -Lactamase

58. Cephalosporin

59. Clinically Important Antibiotics