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  • 1. Antibiotics: Protein Synthesis, Nucleic Acid Synthesis and Metabolism
  • 2. Principles and Definitions <ul><li>Selectivity </li></ul><ul><ul><li>Selectivty   toxicity  </li></ul></ul><ul><li>Therapeutic index </li></ul><ul><ul><li>Toxic dose/ Effective dose </li></ul></ul><ul><li>Categories of antibiotics </li></ul><ul><ul><li>Bacteriostatic </li></ul></ul><ul><ul><ul><li>Duration of treatment sufficient for host defenses </li></ul></ul></ul><ul><ul><li>Bactericidal </li></ul></ul><ul><ul><ul><li>Usually antibiotic of choice </li></ul></ul></ul>
  • 3. Principles and Definitions <ul><li>Selectivity </li></ul><ul><li>Therapeutic index </li></ul><ul><li>Categories of antibiotics </li></ul><ul><ul><li>Use of bacteriostatic vs bactericidal antibiotic </li></ul></ul><ul><ul><ul><li>Therapeutic index better for bacteriostatic antibiotic </li></ul></ul></ul><ul><ul><ul><li>Resistance to bactericidal antibiotic </li></ul></ul></ul><ul><ul><ul><li>Protein toxin mediates disease – use bacteriostatic protein synthesis inhibitor </li></ul></ul></ul>
  • 4. Principles and Definitions <ul><li>Antibiotic susceptibility testing (in vitro) </li></ul><ul><ul><li>Minimum inhibitory concentration (MIC) </li></ul></ul><ul><ul><ul><li>Lowest concentration that results in inhibition of visible growth </li></ul></ul></ul><ul><ul><li>Minimum bactericidal concentration (MBC) </li></ul></ul><ul><ul><ul><li>Lowest concentration that kills 99.9% of the original inoculum </li></ul></ul></ul>
  • 5. Antibiotic Susceptibility Testing 8 4 0 2 1 Tetracycline (  g/ml) MIC = 2  g/ml Determination of MIC Chl Amp Ery Str Tet Disk Diffusion Test
  • 6. Zone Diameter Standards for Disk Diffusion Tests
  • 7. Principles and Definitions <ul><li>Combination therapy </li></ul><ul><ul><li>Prevent emergence of resistant strains </li></ul></ul><ul><ul><li>Temporary treatment until diagnosis is made </li></ul></ul><ul><ul><li>Antibiotic synergism </li></ul></ul><ul><ul><ul><li>Penicillins and aminoglycosides </li></ul></ul></ul><ul><ul><ul><li>CAUTION: Antibiotic antagonism </li></ul></ul></ul><ul><ul><ul><ul><li>Penicillins and bacteriostatic antibiotics </li></ul></ul></ul></ul><ul><li>Antibiotics vs chemotherapeutic agents vs antimicrobials </li></ul>
  • 8. Antibiotics that Inhibit Protein Synthesis
  • 9. Review of Initiation of Protein Synthesis 30S 1 3 2 GTP 1 2 3 GTP Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met-tRNA Spectinomycin Aminoglycosides 1 2 GDP + Pi 50S 70S Initiation Complex A P
  • 10. Review of Elongation of Protein Synthesis GTP A P Tu GTP Tu GDP Ts Ts Tu + GDP Ts Pi P A Tetracycline A P Erythromycin Fusidic Acid Chloramphenicol G GTP G GDP + Pi G GDP A P + GTP
  • 11. Protein Synthesis Microbe Library -American Society for Microbiology www.microbelibrary.org
  • 12. Survey of Antibiotics
  • 13. Protein Synthesis Inhibitors <ul><li>Mostly bacteriostatic </li></ul><ul><li>Selectivity due to differences in prokaryotic and eukaryotic ribosomes </li></ul><ul><li>Some toxicity - eukaryotic 70S ribosomes </li></ul>
  • 14. Antimicrobials that Bind to the 30S Ribosomal Subunit
  • 15. Aminoglycosides (bactericidal) streptomycin , kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) <ul><li>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. </li></ul>
  • 16. Microbe Library American Society for Microbiology www.microbelibrary.org
  • 17. Aminoglycosides (bactericidal) streptomycin , kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) <ul><li>Spectrum of Activity -Many gram-negative and some gram-positive bacteria; Not useful for anaerobic (oxygen required for uptake of antibiotic) or intracellular bacteria . </li></ul><ul><li>Resistance - Common </li></ul><ul><li>Synergy - The aminoglycosides synergize with  -lactam antibiotics. The  -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides. </li></ul>
  • 18. Tetracyclines (bacteriostatic) tetracycline , minocycline and doxycycline <ul><li>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. </li></ul><ul><li>Spectrum of activity - Broad spectrum; Useful against intracellular bacteria </li></ul><ul><li>Resistance - Common </li></ul><ul><li>Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth. </li></ul>
  • 19. Spectinomycin (bacteriostatic) <ul><li>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. </li></ul><ul><li>Spectrum of activity - Used in the treatment of penicillin-resistant Neisseria gonorrhoeae </li></ul><ul><li>Resistance - Rare in Neisseria gonorrhoeae </li></ul>
  • 20. Antimicrobials that Bind to the 50S Ribosomal Subunit
  • 21. Chloramphenicol , Lincomycin, Clindamycin (bacteriostatic) <ul><li>Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. </li></ul><ul><li>Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range </li></ul><ul><li>Resistance - Common </li></ul><ul><li>Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis. </li></ul>
  • 22. Macrolides (bacteriostatic) erythromycin , clarithromycin, azithromycin, spiramycin <ul><li>Mode of action - The macrolides inhibit translocation. </li></ul><ul><li>Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella </li></ul><ul><li>Resistance - Common </li></ul>
  • 23. Microbe Library American Society for Microbiology www.microbelibrary.org
  • 24. Antimicrobials that Interfere with Elongation Factors Selectivity due to differences in prokaryotic and eukaryotic elongation factors
  • 25. Fusidic acid (bacteriostatic) <ul><li>Mode of action - Fusidic acid binds to elongation factor G (EF-G) and inhibits release of EF-G from the EF-G/GDP complex. </li></ul><ul><li>Spectrum of activity - Gram-positive cocci </li></ul>
  • 26. Inhibitors of Nucleic Acid Synthesis
  • 27. Inhibitors of RNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic RNA polymerase
  • 28. Rifampin , Rifamycin, Rifampicin, Rifabutin (bactericidal) <ul><li>Mode of action - These antimicrobials bind to DNA-dependent RNA polymerase and inhibit initiation of mRNA synthesis. </li></ul><ul><li>Spectrum of activity - Broad spectrum but is used most commonly in the treatment of tuberculosis </li></ul><ul><li>Resistance - Common </li></ul><ul><li>Combination therapy - Since resistance is common, rifampin is usually used in combination therapy. </li></ul>
  • 29. Inhibitors of DNA Synthesis Selectivity due to differences between prokaryotic and eukaryotic enzymes
  • 30. Quinolones (bactericidal) nalidixic acid , ciprofloxacin , ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin <ul><li>Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. </li></ul><ul><li>Spectrum of activity - Gram-positive cocci and urinary tract infections </li></ul><ul><li>Resistance - Common for nalidixic acid; developing for ciprofloxacin </li></ul>
  • 31. Antimetabolite Antimicrobials
  • 32. Inhibitors of Folic Acid Synthesis <ul><li>Basis of Selectivity </li></ul><ul><li>Review of Folic Acid Metabolism </li></ul>p-aminobenzoic acid + Pteridine Dihydropteroic acid Dihydrofolic acid Tetrahydrofolic acid Pteridine synthetase Dihydrofolate synthetase Dihydrofolate reductase Thymidine Purines Methionine Trimethoprim Sulfonamides
  • 33. Sulfonamides , Sulfones (bacteriostatic) <ul><li>Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. </li></ul><ul><li>Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. </li></ul><ul><li>Resistance - Common </li></ul><ul><li>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. </li></ul>
  • 34. Trimethoprim , Methotrexate, Pyrimethamine (bacteriostatic) <ul><li>Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. </li></ul><ul><li>Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. </li></ul><ul><li>Resistance - Common </li></ul><ul><li>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. </li></ul>
  • 35. Anti-Mycobacterial Antibiotics
  • 36. Para-aminosalicylic acid (PSA) (bacteriostatic) <ul><li>Mode of action - Similar to sulfonamides </li></ul><ul><li>Spectrum of activity - Specific for Mycobacterium tuberculosis </li></ul>
  • 37. Dapsone (bacteriostatic) <ul><li>Mode of action - Similar to sulfonamides </li></ul><ul><li>Spectrum of activity - Used in treatment of leprosy ( Mycobacterium leprae ) </li></ul>
  • 38. Isoniazid (INH) (bacteriostatic ) <ul><li>Mode of action - Isoniazid inhibits synthesis of mycolic acids. </li></ul><ul><li>Spectrum of activity - Used in treatment of tuberculosis </li></ul><ul><li>Resistance - Has developed </li></ul>
  • 39. Antimicrobial Drug Resistance Principles and Definitions <ul><li>Clinical resistance vs actual resistance </li></ul><ul><li>Resistance can arise by mutation or by gene transfer ( e.g. acquisition of a plasmid) </li></ul><ul><li>Resistance provides a selective advantage </li></ul><ul><li>Resistance can result from single or multiple steps </li></ul><ul><li>Cross resistance vs multiple resistance </li></ul><ul><ul><li>Cross resistance -- Single mechanism-- closely related antibiotics </li></ul></ul><ul><ul><li>Multiple resistance -- Multiple mechanisms -- unrelated antibiotics </li></ul></ul>
  • 40. Antimicrobial Drug Resistance Mechanisms <ul><li>Altered permeability </li></ul><ul><ul><li>Altered influx </li></ul></ul><ul><ul><ul><li>Gram negative bacteria </li></ul></ul></ul>
  • 41. Microbe Library American Society for Microbiology www.microbelibrary.org
  • 42. Antimicrobial Drug Resistance Mechanisms <ul><li>Altered permeability </li></ul><ul><ul><li>Altered efflux </li></ul></ul><ul><ul><ul><li>tetracycline </li></ul></ul></ul>Microbe Library American Society for Microbiology www.microbelibrary.org
  • 43. Antimicrobial Drug Resistance Mechanisms <ul><li>Inactivation </li></ul><ul><ul><li> -lactamase </li></ul></ul><ul><ul><li>Chloramphenicol acetyl transferase </li></ul></ul>Microbe Library American Society for Microbiology www.microbelibrary.org
  • 44. Antimicrobial Drug Resistance Mechanisms <ul><li>Altered target site </li></ul><ul><ul><li>Penicillin binding proteins (penicillins) </li></ul></ul><ul><ul><li>RNA polymerase (rifampin) </li></ul></ul><ul><ul><li>30S ribosome (streptomycin) </li></ul></ul>Microbe Library American Society for Microbiology www.microbelibrary.org
  • 45. Antimicrobial Drug Resistance Mechanisms <ul><li>Replacement of a sensitive pathway </li></ul><ul><ul><li>Acquisition of a resistant enzyme (sulfonamides, trimethoprim) </li></ul></ul>

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