1. Chemotherapeutic Agents Antimicrobials and Antibiotics

2. Normal Microbiota Body Cavities Closed = free of microbes Open = normal flora Regions Skin Mouth (teeth/gums) GI Genitourinary Upper = sterile Perineum

3. Bacterial Groups

4. Microbial Pathogenicity Cause of disease Means Invasiveness Toxigenesis Stages Colonization Adherence Nonspecific (dock) Specific (anchor) Invasion Enzymes  Spread  Digest Toxins

5. Definitions Chemotherapy Antimicrobials Antibiotics Synthetic Drugs Selective Toxicity

6. Paul Ehrlich

7. Antibiotic Development AB Natural Source Fungal molds Bacteria  Bacillus  Actinomycetes Chemotherapeutic Chemical Semi-synthetic Hybrid

8. Drug Basics Classification Chemtherapeutic Pharmacodynamic Miscellaneous Names (3+) Chemical Brand/Trade Generic Sites of Action Enzyme inhibition Receptor interactions Non-specific (i.e pH) Modes of Action (MOA) Pharmakokinetics Stimulate/Depress/Kill Effects Theruapeutic Adverse

9. Antimicrobial Characteristics Toxicity MOA Spectrum BS (both GP and GN) NS (GP or GN) Limited spectrum Target Tissue Adverse Effects Resistance Route of Administration

10. Mechanism of Action (MOA)

11. Effectiveness of AB Route of Administration Uptake Clearance Susceptibility Dosage Exceed MIC Therapeutic Selective Toxicity

12. Adverse Drug Reactions (ADR)

14. AB and Sx

15. Other Drug Considerations Availability Stability Cost

16. MOA Cell Wall Cell Membrane DNA Protein Synthesis 30S 50S Metabolites

17. Antimicrobial Resistance Natural (Inherent) G(-) LPS Lack target or transport Acquired Mutation Horizontal transfer Vertical Horizontal Transformation Transduction Conjugation

18. Plasmids

19. R-Plasmid

20. AB resistance

21. “Super Bugs”

22. Kirby-Bauer Disk Diffusion MH agar AB disks MIC Table Zone diameter Classified Susceptible Intermediate Resistant

25. Metabolite Inhibition

26. Sulfa Drugs

27. Sulfonamides Sulfa-; Sulpha- Antimetabolites Structural Analogs Decrease folic acid Bacteriostatic Side Effects Allergic KCS

28. PABA Competitive Enzyme Inhibition PABA  Folic Acid Folic Acid (B vitamin) Synthesis of N bases TMPS actions as above Trimethoprim inhibits conversion of folic acid to its active form

29. Antimetabolite Action

30. TMPS BS Block pathway of synthesis for tetrahydrofolic acid No DNA No RNA Competitive antagonism Sulfa  first enzyme Trimethoprim  3 rd enzyme Synergistic

31. Cell Wall Synthesis Inhibitors

32. Sir Alexander Fleming

33. Beta-Lactams

34. Penicillin Family Beta-lactams Penicillium mold source -cillin MOA Inhibits PGC synthesis Prevents cross-linking by transpeptidase Mimicks D-alanine at active enzyme site Bacteriocidal G(+) Adverse Rxn = allergies Penicillin G, Penicillin V, Oxacillin, Ampicillin, Cloxacillin, Ticarcillin, Nafcillin, Dicloxacillin, Carbenicillin

35. Inhibition of Cell Wall Synthesis Prevent cross linking Binds to transpeptidases Add new monomers Reseal wall Osmotic Lysis Bacterial Resistance Penicillinase MRSA VRSA Beta Lactamases Cephalosporinases

37. Beta-Lactam Inhibition

38. Beta-Lactamase Inhibitors Clavulanic acid Noncompetitive inhibitor of penicillinase Destroys enzyme

39. Carbapenems -penem Imipenem Beta-lactam BS Cell wall synthesis

40. Cephalosporins Modified B-lactam ring (6) Modified R groups Sewer fungus source Generations 1 st 2 nd 3 rd 4 th Cepha- or cef- Broad Spectrum; Bacteriocidal MOA Binds to transpeptidases No cross linking of NAM-NAM Prevents resealing Weak  osmotic lysis

41. Cephalosporin Family 1 st Cefalixin Cephadroxil 2 nd Cefaclor Cefoxitin 3 rd Cefdinir Deftibuten 4 th

42. Glycopeptides Examples Vancomycin Teichoplanin MOA Bind to cell wall peptides Block cross-linking of transpeptidases (Alanine-Alanine) Blocks transglycolation NAM-NAG bond Result Weak cell wall Osmotic lysis Bacteriocidal GP VRSA has developed

43. Polypeptides Some can inhibit cell wall synthesis Inhibit PGC subunit release from carrier Inhibits teichoic acid synthesis Example Bacitracin NS: GP Topic Use Skin Ophthalmic

44. Bacitracin MOA Bactoprenol assembles new monomers for the cell wall in the PM Bacitracin binds to Bactoprenol in PM Blocks dephosphorylation (must loose 2 nd Phosphate) No monomers can inserted into cell wall Osmotic lysis

45. Inhibition of AFB MOA Disrupt cell wall synthesis Cycloserine Prevents replication Clofazimine Disrupt Waxy layer Mycolic acid and Arabinogalactan  Examples  Isoniazid  Ethambutal Mycobacterium Multidrug Therapies

46. TB resistance

47. Ribosomes

48. Protein Synthesis Steps Transcription DNA mRNA RNA polymerase Translation Initiation mRNA 30S 50S Elongation P site A site Translocation Peptide bond formation Termination

49. Protein Synthesis Inhibition

50. 50S Inhibition

51. Chloramphenicol CHPC BS Synthetic MOA Attaches to 50S ribosome Interferes with peptide bonds Results Inhibits protein synthesis Side Effects Aplastic anemia Can inhibit mitochondrial protein synthesis

52. Macrolides -mycin (usually) Actinomyces source Examples Erythromycin Azithromycin Clarithromycin Dithromycin MOA 50S reversible binding Inhibits elongation Blocks translocation Result Inhibit protein synthesis G(+) and select G(-) [resp] Erythromycin

53. Macrolide MOA

54. Lincosamides Semisynthetic Actinomyces source Example Clindamycin Lincomycin G(+), some anaerobes MOA Bind to 50S Block elongation Inhibits protein synthesis

55. Streptogramins Two Groups A: nonpeptide B: cyclic peptides Examples A: Dalfopristin B: Quinupristin MOA Group A Distort ribosomes Prevent tRNA binding Group B Block translocation Results Inhibit protein synthesis Synergistic if both groups used

56. 30S Inhibition

57. Aminoglycosides -mycin (usually) Streptomyces source NS: G(-) but some have BS Examples Streptomycin Gentamicin Neomycin Amikacin Tobramycin MOA Binds to 30S, irreversibly Changes shape of 30S 50S can not bind Interferes with initiation Misreads mRNA codons Wrong AA inserted by tRNA Results Inhibit protein synthesis by interfering with translation Side Effects Toxicity CN 8 Kidney

58. Tetracyclines -cycline Streptomyces source BS GN, GP Rickettsial organisms Examples Tetracycline Doxycycline (semi-synthetic) Oxytetracycline Tigecycline Minocycline MOA Bind to 30S subunit reversibly Block tRNA attachment at A site Inhibit codon-anticodon interaction Result Inhibit protein synthesis Side effects Affect bone development Stain teeth in children

59. Tetracycline MOA

60. Tetracycline Resistance

61. Oxazolidinones New AB -zolid Example Linezolid MOA Prevents 30S-50S assembly Interferes with mRNA Disrupts initiation Results Inhibits translation Use G(+) MRSA / VRSA

62. Ribosome Inhibition Summary

63. Bacterial Resistance Pump out AB (efflux) Methylate Ribosomes Obscure target Block binding site Modify AB so it can’t bind to ribosome target

64. Nucleic Acid Inhibition

65. Quinolones Generations 1 st 2 nd 3 rd 4th Examples Naldixic acid MOA Block A subunit of DNA gyrase Results Bactericidal GN

66. Fluroquinolones -floxacin Second generation quinolone Examples Levofloxacin Norfloxacin MOA Bind to DNA gyrase Bind to Tropoisomerase IV Result: Blocks DNA Repair Replication Transcription Bacteriocidal BS DNA gyrase

68. Adverse Effects

69. Bacterial Resistance Modify DNA gyrase Bacterial synthesis of sort DNA segments to trick quinolones

70. Metronidizole Activated by bacteria Nicks in DNA to fragment strand Used in anaerobic infections Trade Name Flagyl

71. Rifampin Semi-synthetic GN and Mycobacteria Example Rifampicin MOA Binds to RNA polymerase Results Prevents transcription

72. Plasma Membrane Disruption

73. Polypeptides Example Polymixins Polymixin B Polymixin E (colistin) MOA Detergents Replace Mg++ and Ca++ Damage phospholipids Binds to Lipid A Results Alter PM Cell contents leak out

74. Antibiotic MOA Summary

76. Antifungals

78. Polyenes MOA Inactivatate sterols Changes membrane permeability Leakage of interacellular components Examples Amphotericin Nystatin Results Antifungal -static -cidal Dose dependant

79. Fungal Cell Walls

80. Helminths

82. Protozoa

85. Pentamide MOA Binds to prokaryote DNA Inhibits transcription and translation Antiprotozoal Examples Pentamide Pentam Pneumopent

86. Antivirals

89. Antisense Nucleic Acids MOA ssDNA or ssRNA binds as complementary strand to mRNA Blocks translation Examples Fomivirsen Use CMV

90. Questions?