Understanding Antibiotics: Mechanisms and Resistance

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

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  3rd 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 • 1st • 2nd • 3rd • 4th • Cepha- or cef- • Broad Spectrum; Bacteriocidal • MOA • Binds to transpeptidases • No cross linking of NAM-NAM • Prevents resealing • Weak  osmotic lysis

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

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 2nd 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