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Protein Synthesis Inhibitors

Protein Synthesis Inhibitors. Tetracyclines Macrolides Chloramphenicol Aminoglycosides Clindamycin Streptogramins. Alan M. Reynared, Ph.D. QUICK REVIEW - Protein Synthesis. Tetracyclines - Structure. Excretion R 1 R 2 R 3 R 4 mg/hr

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Protein Synthesis Inhibitors

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  1. Protein Synthesis Inhibitors Tetracyclines Macrolides Chloramphenicol Aminoglycosides Clindamycin Streptogramins Alan M. Reynared, Ph.D.

  2. QUICK REVIEW - Protein Synthesis

  3. Tetracyclines - Structure Excretion R1 R2 R3 R4 mg/hr tetracycline (Achromycin) H OH CH3 H 65 chlortetracycline (Aureomycin) H OH CH3 Cl 32 oxytetracycline (Terramycin) OH OH CH3 H 90 demethylchlortetracycline (Declomycin) H OH H Cl 35 doxycycline (Vibramycin) OH CH3 H H 16 minocycline (Minocin) H H H N(CH3) 9

  4. Tetracyclines - Uses Gram- Bacteria  Helicobacter pylori (duodenal ulcer)  Borrelia recurrentis (Lyme disease, relapsing fever) Other Organisms  Mycoplasma pneumoniae  acne

  5. Tetracycline - Mechanism  Inhibits protein synthesis  Static  Chelates divalent cations -- Ca++, Mg++

  6. Tetracycline - Adverse Effects  headache, nausea, vomiting  discoloration of bones and teeth  photosensitivity  liver damage  superinfection

  7. Superinfection A new infection appearing during treatment for a primary infection The organism will be resistant to the antibiotic used for the primary infection Organisms causing superinfection Staphylococcus aureus - enterocolitis Candida albicans - vagina, mouth Clostridium difficile - pseudomembranous colitis Risk factors in hospital > 6 days 6 > age > 60 broad spectrum antibiotic

  8. Tetracylines  Administration Oral administration but interference by food, Ca++, Mg++  Excretion renal, fecal enterohepatic

  9. Chloramphenicol - structure/features Features  Broad Spectrum  Inexpensive  Oral administration  Virtually non-toxic

  10. Chloramphenicol - uses/toxicity Uses  Haemophilus influenzae (meningitis)  Typhus  Rocky Mountain Spotted Fever  eye infections Adverse Effects  superinfection  aplastic anemia

  11. Chloramphenicol - mechanism  Inhibits protein synthesis  Static

  12. Macrolides - structure / names erythromycin azithromycin clarithromycin

  13. Macrolides - uses whooping cough pharyngitis Community-acquired pneumonia Penicillin-allergic patients staphylococcus streptococcus pneumococcus

  14. Macrolides - mechanism  Inhibits protein synthesis  Static

  15. Macrolides - toxicity / drug interactions Toxicity  nausea, vomiting, diarrhea  cholestatic hepatitis (esp. estolate) Drug Interactions  inhibit P450 system

  16. Macrolides Administration  erythromycin destroyed by gastric acid - enteric coated tablets - erythromycin stearate - erythromycin estolate  food decreases absorption of all macrolides

  17. Aminoglycosides - structure / names streptomycingentamicin kanamycin tobramycin neomycin netilmicin paromomycin amikacin spectinomycin

  18. Aminoglycosides - uses Amikacin  serious Gram-negative infections  endocarditis (+ a penicillin or cephalosporin) Streptomycin  plague (Yersinia pestis)  tuleremia (Francisella tulerensis)  tuberculosis (Mycobacterium tuberculosis)

  19. Aminoglycosides - mechanism  inhibits protein synthesis  ribosomal binding is very tight  cidal  at high doses  bacterial cell permeability

  20. Aminglycosides - adverse effects - deafness - vertigo - kidney damage

  21. Aminoglycosides - spectinomycin Use Reserve drug for gonorrhea

  22. Clindamycin USES  Staphylococcus aureus  Streptococcus pyogenes  Bacteroides fragilis  Clostridium tetani

  23. Clindamycin - mechanism  Inhibits protein synthesis  static

  24. Clindamycin - adverse effects superinfection pseudomembranous colitis (ulcerative colitis) Clostridium difficile

  25. Streptogramins Synercid  synergistic combination quinupristin dalfopristin  activity against staphylococci streptococci vancomycin-resistant enterococci (VRE)

  26. Drug Resistance Types of resistance chromosomal plasmid-mediated Mechanisms of resistance enzymatic destruction of drug altered target of drug decreased influx of drug increased efflux of drug

  27. Drug Resistance 1955 - epidemic of dysentary in Tokyo Multiple Drug Resistance streptomycin 10-8 tetracycline 10-8 chloramphenicol 10-8 sulfisoxazole 10-8 all four 10-32 Transmissible Drug Resistance patient excreting MDR S. dysenteriae and E. coli

  28. Drug Resistance Bacterial Conjugation

  29. Drug Resistance Plasmid specifying resistance to 2 antibiotics

  30. Drug Resistance MDR spread rapidly all over the world

  31. Drug Resistance Increase in resistance with increased production of antibiotics

  32. Drug Resistance - specific antibiotics penicillin -lactamase altered penicillin-binding protein aminoglycosides acetylation AcCoA + AG AcAG + CoA phosphorylation ATP + AG P-Ag + ADP adenylylation ATP + AG AMP-Ag + PPi

  33. Drug Resistance - specific antibiotics chloramphenicol acetylation AcCoA + CM AcCM + CoA erythromycin altered ribosome tetracycline active efflux of drug

  34. Drug Resistance - aminoglycosides

  35. Sulfonamides Gerhard Domagk, 1895 - 1964 V.P., I. G. Farbenindustrie

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