Protein synthesis inhibitors:

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Protein synthesis inhibitors Chloramphenicol,
Tetracyclines, Macrolides, Clindamycin
Streptogramins Oxazolidinones
Pawitra Pulbutr, M.Sc. In Pharm (Pharmacology)
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  Protein synthesis inhibitors ??????
  chloramphenicol, tetracyclines, macrolides,
  clindamycin, streptogramins, oxazolidinones,
  ketolides ???

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Bacterial protein synthesis
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Drug acting as protein synthesis inhibitors

• Chloramphenicol
• Tetracyclines
• Macrolides
• Clindamycin
• Ketolides
• Oxazolidinones
• Streptogramins
• Aminoglycosides
• Spectinomycin

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Chloramphenicol

• First synthetic antibacterial
• Mechanism of action
• Bind with 50s subunit
• Inhibit peptidyl transferase
• Inhibit transpeptidation connection of peptide
  from P-site to A-site
• Bacteriostatic
• Bactericidal to some bacteria gtgtgtH. influenzae,
  N. meningitidis, bacteroides
• Resistance
• Decrease uptake
• Chloramphenicol acetyl transferase enzyme
  destroy

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Clinical uses

• Serious rickettsial infection
• Typhus alternative to doxycycline
• Bacterial meningitis (due to PRSP,
  meningococcus) alternative to penicillin
• Eye infection .. Topical
• Melioidosis Burkholderia pseudomalleri (gram
  negative rods)

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ADRs

• GI disturbance.. n/v, diarrhea, oral-vaginal
  candidiasis
• Bone marrow supression dose dependentgt 50
  mg/kg/day for 1-2 wks
• Aplastic anemia idiosyncratic reaction not
  dose dependent 1 in 24,000-40,000 . Fetal
  reaction
• Unexplained infection/ Bleeding/ Fatigue
• Toxicity for newborn
• Immature conjugation
• Gray baby syndrome vomiting, flaccidity,
  hypothermia, gray color, shock, death
• Not gt 50 mg/kg in infants , gt 25 mg in immatures

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Tetracyclines

• chlortetracycline
• oxytetracycline
• tetracycline
• demeclocycline
• methacycline
• doxycycline
• minocycline

Hydrochloride salt more water soluble All
chelates with divalent metal ions
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Mechanism of action

• Bind with 30 s subunit
• Inhibit binding of aminoacyl-tRNA to A-site
• Inhibit protein synthesis
• Bacteriostatic

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Spectrum

• Broad spectrum
• gram positive, negative, anaerobes
• rickettsiae
• chlamydia
• mycoplasma
• protozoa (ameba, plasmodium)

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Clinical uses

• DOC for Mycoplasma pneumonia, Chlamydia,
  Rickettsia infection
• Acne
• Bronchitis
• Community acquired pneumonia
• Lyme disease
• Leptospirosis
• Vibrio infection
• Atypical mycobacterial infection
• H. pyroli infection Gastric ulcer
• Protozoal infection
  E. histolytica, Plasmodium (malaria)

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Macrolides

• Macrocyclic lactone ring
• Erythromycin
• Roxithromycin
• Clarithromycin
• Azithromycin

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Mechanism of action

• Bind 50s subunit
• Inhibit aminoacyl translocation
• Inhibit translocation of tRNA from
  A-site to P-site
• Resistance
• Decrease uptake or Efflux pump
• Produce esterase enzyme destroy drugs
• Alteration of ribosomal binding site . Methylase
  MLS-B

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Clinical uses

• DOC for
• Corynebacterium infection (diphteria,
  corynebacterial sepsis, erythasma)
• Respiratory, neonatal, ocular, genital
  Chlamydial infection
• Community acquired pneumonia
• Pneumococci
• Mycoplasma
• Legionella

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• Alternative to penicillin in..
• streptococci
• staphylococci
• pneumococci

• pharyngitis
• skin soft tissue infection
• pneumonia

Many are resistant to macrolide too!!

• Endocarditis prevention in valvular heart
  disease pt undergoes dental surgery

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Ketolides

• Telithromycin
• Macrolide like macrocyclic lactone ring
• 3- keto group
• No L-cladinose sugar
• Macrolide like mechanism of action
• Bind to 50s subunit
• Higher affinity

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Spectrum

• RTI caused by beta-lactam, macrolide,
  tetracyclines, co-trimoxazole resistant bacteria
• S. pneumoniae
• H. influenzae
• M. catarrhalis
• Effective to MLS-B resistance
• No MLS-B inducer

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Clindamycin

• Cl derivative of lincomycin
• Erythromycin like mechanism of action bind at
  50 s subunit
• Erythromycin binding site
• Spectrum
• Streptococci
• Staphylococci
• Pneumococci
• Bacteroides Other anaerobes
• Not effective to gram negative
  (poor permeability) , enterococci, Clostridium
  difficile

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Streptogramins

• Quinupristin-dalfopristin (Synercid)
• Quinupristin Streptogramin B 30
• Dalfopristin Streptogramin A 70
• Macrolide like mechanism of action bind at 50s
  subunit
• Spectrum
• Gram positive bacteria
• Multidrug resistant streptococci
• Penicillin resistant pneumococci (PRSP)
• MRSA
• Enterococcus faecium (not E. faecalis)
• Not to gram negative

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Clinical uses . IV infusion

• Vancomycin resistant E. faecium (VRE) infection
• MRSA infection
• Streptococci infection
• Penicillin resistant/ susceptible pneumococci
  infection

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Oxazolidinones

• Linezolid (Zyvox)
• Mechanism of action
• Bind at 23s rRNA of 50s subunit
• Inhibit Ribosomal assembly
• Unique binding site No cross resistance
• Time dependent killing
• Spectrum
• Gram positive which resistant to other drugs
• Staphylococci, Streptococci, Enterococci
• Gram positive anaerobes, rods
• MRSA,VRE, PRSP
• No activity on gram negative

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Clinical use

• VRE infection
• Other multidrug resistant

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Tetracyclines Bind at 30s subunit
Chloramphenicol bind at 50s
Oxazolidinones bind at 23s rRNA
Macrolides/ Ketolides/ Clindamycin/
Streptogramins Bind at 50s subunit
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THE END