Antibiotics Lecture 03

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Antibiotics Lecture 03

  1. 1. Bio 319: Antibiotics Lecture Three Topic: Inhibitors of cell wall synthesis (brief) Inhibitors of protein biosynthesis Lecturer: Dr. G. Kattam Maiyoh13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 1
  2. 2. Inhibitors of Cell Wall Synthesis13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 2
  3. 3. Carbapenems • Beta-lactam ring is fused to a 5 member ring system • Effect on microbes and pharmacology of carbapenems similar to penicillins13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 3
  4. 4. Selected Carbapenems• Imipenem – Broad spectrum including anaerobes and Pseudomonas aeruginosa – Parentally administered – Must be combined with cilastatin to be absorbed – Excreted by kidneys• Meropenem, ertapenem, and doripenem are similar to imipenem but don’t need co- administration with cilastatincilastatin chemical compound which inhibits the human enzyme dehydropeptidase13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 4
  5. 5. Toxicity/Contraindications of Carbapenems• Nausea and vomiting (common)• Hypersensitivity reactions (uncommon) – Essentially the same as for penicillins, exception is the monobactam – Cross-reactivity is possible, exception is the monobactam GKM/BIO319:Antibiotics/Lec.13/02/2013 5 03/Sem02/2013
  6. 6. Aztrenam – a monobactam• Works only on Gm -ve, including Pseudomonas aeruginosa• Useful for treating G-ve infections that require a beta-lactam because it does not elicit hypersensitivity reactions• Monobactam - beta-lactam compounds wherein the beta-lactam ring is alone and not fused to another ring13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 6
  7. 7. Beta-lactamase inhibitors a. Clavulanic acid – Irreversible inhibitor of β-lactamase – Good oral absorption – Combined with amoxicillin or ticarcillin b. Sulbactam13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 7
  8. 8. Peptide AntibioticsPeptide Antibiotics are drugs with polypeptides structureSub-group of Peptide Antibiotics Polymyxins Glycopeptides Bacitracin StreptograminsEach drug group has its own mechanism of action 4 groups and 4 mechanism13/02/2013 GKM/BIO319:Antibiotics/Lec. 8 03/Sem02/2013
  9. 9. • Peptide antibiotics – May be further classified as follows; –Polymyxins »Polymyxin B »Colistin –Glycopeptides »Vancomycin »Teicoplanin »Avoparcin –Bacitracin GKM/BIO319:Antibiotics/Lec.13/02/2013 9 03/Sem02/2013
  10. 10. Polymyxins Drug members Polymyxin B Colistin (Polymyxin E) Mechanism of action Detergent-like action Damage to cell membrane function Bind to LPS and destroy outer membrane of Gram-negative bacteria Bactericidal Concentration-dependent Non-selective on bacterial membrane Spectrum of activity Gram-negative bacteria GKM/BIO319:Antibiotics/Lec.13/02/2013 10 03/Sem02/2013
  11. 11. Polymyxins• Pharmacokinetics – Not absorbed via GI tract – If injection, drug accumulated and slowly excreted• Toxicities – Highly toxic if systemic injection – Nephrotoxic – Neurotoxic• Clinical uses – Oral treatment – Local treatment GKM/BIO319:Antibiotics/Lec.13/02/2013 11 03/Sem02/2013
  12. 12. Glycopeptides • Group members – Vancomycin • Antibacterial activity – Inhibition of cell wall synthesis – Active against Gram-positive bacteria • Not absorbed orally, must administered IV • High toxicity – Local irritation , ototoxicity, nephrotoxicity • Clinical uses – Hardly used in animals – Used only resistant case i.e. to beta-lactams GKM/BIO319:Antibiotics/Lec.13/02/2013 12 03/Sem02/2013
  13. 13. Bacitracin• Only member is Bacitracin• Drug activity – Inhibit cell wall synthesis – Activity on Gram-positive bacteria – Bactericidal• Nephrotoxic if systemic injection• Clinical uses – the same as polymyxin – Oral – as growth promoter – Local or topical drugs GKM/BIO319:Antibiotics/Lec.13/02/2013 13 03/Sem02/2013
  14. 14. Antibiotics that Inhibit Protein Synthesis GKM/BIO319:Antibiotics/Lec.13/02/2013 14 03/Sem02/2013
  15. 15. Protein synthesis inhibitors – Aminoglycosides – Tetracyclins _Spectinomycin – Macrolides – Chloramphenicol – Clindamycin GKM/BIO319:Antibiotics/Lec.13/02/2013 15 03/Sem02/2013
  16. 16. Inhibition of Protein Synthesis by Antibiotics GKM/BIO319:Antibiotics/Lec.13/02/2013 16 03/Sem02/2013 Figure 20.4
  17. 17. Review of Initiation of Protein Synthesis 1 3 30S 2 GTP 1 2 3 GTP Initiation Factors f-met-tRNA mRNA Spectinomycin 3 GDP + Pi 50S 2 P A 1 1 2 GTP 70S Aminoglycosides 30S Initiation Initiation GKM/BIO319:Antibiotics/Lec. Complex13/02/2013 03/Sem02/2013 Complex 17
  18. 18. Review of Elongation of Protein Synthesis P A Tetracycline P A Tu GTP Tu GDP + Pi GTP Ts Ts Tu Ts GDP Chloramphenicol GDP Fusidic Acid + GTP G G GDP + Pi G GTP P A P A Erythromycin GKM/BIO319:Antibiotics/Lec.13/02/2013 18 03/Sem02/2013
  19. 19. Survey of Antibiotics GKM/BIO319:Antibiotics/Lec.13/02/2013 19 03/Sem02/2013
  20. 20. Protein Synthesis Inhibitors• Mostly bacteriostatic• Selectivity due to differences in prokaryotic and eukaryotic ribosomes• Some toxicity - eukaryotic 70S ribosomes13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 20
  21. 21. Antimicrobials that Bind to the 30S Ribosomal Subunit GKM/BIO319:Antibiotics/Lec.13/02/2013 21 03/Sem02/2013
  22. 22. a) 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. GKM/BIO319:Antibiotics/Lec. 13/02/2013 22 03/Sem02/2013
  23. 23. Microbe Library American Society for Microbiology www.microbelibrary.org GKM/BIO319:Antibiotics/Lec.13/02/2013 23 03/Sem02/2013
  24. 24. b) Aminoglycosides (bactericidal) streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) • Spectrum of Activity –Effective against 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 β -lactam antibiotics. The β -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 24
  25. 25. c) 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. GKM/BIO319:Antibiotics/Lec.13/02/2013 25 03/Sem02/2013
  26. 26. d) 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 GKM/BIO319:Antibiotics/Lec.13/02/2013 26 03/Sem02/2013
  27. 27. Antimicrobials that Bind to the 50S Ribosomal Subunit GKM/BIO319:Antibiotics/Lec.13/02/2013 27 03/Sem02/2013
  28. 28. a) 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. GKM/BIO319:Antibiotics/Lec.13/02/2013 28 03/Sem02/2013
  29. 29. b) Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin, spiramycin • Mode of action - The macrolides inhibit translocation. • Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella • Resistance - Common GKM/BIO319:Antibiotics/Lec.13/02/2013 29 03/Sem02/2013
  30. 30. Macrolides : Classification• Macrolides are drugs with lactone ring structure• Sub-groups are based on no. of ring atom – 12-membered ring macrolides – 13-membered – 14-membered (many drugs) – 15-membered – 16-membered (many drugs)• Special groups – Azalides – name for 15-membered – Triamilides – name for tulathromycin (combination of 13- and 15-membered) – Ketolides – name for 14-membered with 3 keto group
  31. 31. MacrolidesDrug examples13-membered Tulathromycin (Triamilides)14-membered Erythromycin Clarithromycin, Roxithromycin, Dirithromycin15-membered Azithromycin (Azalides) Tulathromycin (Triamilides)16-membered Spiramycin Tylosin
  32. 32. Macrolides – general properties• Mechanism of action – Inhibit protein synthesis – Bind to 50S ribosomal unit – Bacteriostatic• Spectrum of activity – Gram-positive – Some Gram- negative
  33. 33. Macrolides Pharmacokinetics Broad distribution in body tissues High intracellular concentration
  34. 34. MacrolidesAdditional properties of Macrolides• Anti-inflammatory effect – Inhibitory effect on neutrophils – inhibit proinflammatory cytokines – Useful for treatment of inflammatory
  35. 35. Erythromycin• Erythromycin is a standard or basic drug of macrolides• Other drug members are usually compared with erythromycin• Important adverse effect - severe diarrhea – Especially in adult horse and ruminants• Clinical uses – Second choice (alternative drug) – Small animals – Fowls – Some cases in ruminants – Not used in pigs
  36. 36. Tylosin and Spiramycin • Tylosin and Spiramycin – Activities are similar to erythromycin – Good activity on Mycoplasma • Clinical uses – Macrolides used in ruminants and pigs – Used for Mycoplasma infection
  37. 37. Advanced generation MacrolidesExample drugs Roxithromycin Dirithromycin Clarithromycin AzithromycinGeneral activity – the same as erythromycinBetter Pharmacokinetic properties Acid stable Fewer GI side effect Higher oral availability Longer serum half-lives Higher tissue concentrations
  38. 38. Ketolides• Ketolides are 14- membered ring macrolides with 3 keto group• Specific drugs – Telithromycin – Cethromycin (still in clinical study)• Important properties – Less resistance – Good activities on
  39. 39. Antimicrobials that Interfere with Elongation Factors Selectivity due to differences in prokaryotic and eukaryotic elongation factors GKM/BIO319:Antibiotics/Lec.13/02/2013 39 03/Sem02/2013
  40. 40. 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 cocci13/02/2013 GKM/BIO319:Antibiotics/Lec. 03/Sem02/2013 40

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