Download to read offline
![Protein synthesis inhibitors [autosaved]](https://cdn.slidesharecdn.com/ss_thumbnails/proteinsynthesisinhibitorsautosaved-190403091041-thumbnail.jpg?width=640&height=640&fit=bounds)
protein synthesis inhibitor .pptx
- 1. Protein synthesis inhibitors Presenter:Dr Umesh Kumar Maurya Department of Pharmacology & Therapeutics King George’s Medical University Lucknow, Uttar Pradesh, India.
- 2. Protein synthesis • Step1. charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome • Step 2. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid • Step 3. The uncharged tRNA left at the donor site is released, and the new 6-amino acid chain with its tRNA shifts to the peptidyl site
- 3. Protein synthesis inhibitors •AMINOGLYCOSIDES (bactericidal) • TETRACYCLINES (bacteriostatic) • CHLOROAMPHENICOL, CLINDAMYCIN (bacteriostatic) • MACROLIDES (bacteriostatic) • LINCOMYCIN (bacteriostatic) • LOINEZOLID( variable) 30S INHIBITORS 50S INHIBITORS
- 4. Tetracycline • Broad spectrumantibiotics • All tetracyclines are obtained from soil actinomycetes • First to be introduced was chlortetracycline in 1948 under the name aureomycin (golden yellow colour of S. aureofaciens colonies producing it) • These are a class of antibiotics having a nucleus of four cyclic rings
- 5. Examples- • Chlortetracycline • Oxytetracycline •Demeclocycline • Doxycycline • Minocycline
- 6. Mode of action •It is bacteriostatic • Inhibit protein synthesis • Bind to 30s ribosome
- 7. Pharmacokinetics • Absorption: oldertetracyclines are incompletely absorbed from GI, absorption is better if taken in empty stomach • Distribution: They are concentrated in liver, spleen and bind to the connective tissue in bone and teeth. • Metabolism: partly metabolized and enter bile • Excretion: excreted in urine by glomerular filtration; dose has to be reduced in renal failure (except doxycycline) ADMINISTRATION AND FATE OF TETRACYCLINE
- 8. Therapeutic applications oftetracycline
- 9.
- 10. Resistance to Tetracycline Resistanceto tetracyclines develops slowly in a graded manner The three main resistance mechanisms are: 1. Concentrating mecha nism becomes less efficient or the bacteria acquire capacity to pump it out 2. Plasmid mediated synthesis of a ‘protection’ protein which protects the ribosomal binding site from tetracycline 3. Enzymatic inactivation of tetracyclines
- 11. Chloramphenicol • Chloramphenicol, anantibiotic produced by Streptomyces venezuelae • It is a yellowish white crystalline solid, aqueous solution is quite stable, stands boiling, but needs protection from light • The nitrobenzene moiety of chloramphenicol is probably responsible for the antibacterial activity as well as its intensely bitter taste
- 12. Mode of action •Chloramphenicol inhibits bacterial protein synthesis by interfering with the ‘transfer’ of the elongating peptide chain to the newly attached aminoacyl-tRNA at the ribosome-mRNA complex • It specifically attaches to the 50S ribosome near the acceptor (A) site and prevents peptide bond formation between the newly attached amino acid and the nascent peptide chain without interfering with the aminoacyl-tRNA attachment to the 30S ribosome
- 13. Pharmacokinetics DRUG INTERACTION ADMINISTRATIONAND FATE OF CHLORAMPHENICOL
- 14. Resistance to Chloramphenicol •Resistance to chloramphenicol is usually caused by a plasmid-encoded acetyltransferase that inactivates the drug • Resistance can also result from decreased permeability and ribosomal mutation • Acetylated derivatives of chloramphenicol fail to bind to bacterial ribosomes
- 15. Adverse effect 1. GIdisturbance 2. Jaundice 3. Ototoxicity 4. Gray baby syndrome
- 16. Clinical Use • Pyogenicmeningitis • Anaerobic infections • Intraocular infections • . Enteric fever • . Conjunctivitis
- 17. Macrolides • Characterized bya macrocyclic lactone ring (usually containing 14 or 16 atoms) to which deoxy sugars are attached • Erythromycin (first member) was discovered in 1950 from metabolic products of a strain of streptomyces erythraeus • Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin
- 18. Mode of action •Macrolides bind to the 50S ribosomal subunit of bacteria but not to the 80S mammalian ribosome; this accounts for its selective toxicity • Binding to the ribosome occurs at a site near peptidyl transferase, with a resultant inhibition of Translocation, Peptide bond formation, Release of oligopeptidyl tRNA
- 19. Antimicrobial Activity • Erythromycinusually is bacteriostatic but may be bactericidal in high concentrations against susceptible organisms • The antibiotic is most active in vitro against aerobic gram-positive cocci and bacilli • In addition, Campylobacter, Legionella, Branhamella catarrhalis, Gardnerella vaginalis, and Mycoplasma, that are not affected by penicillin, are highly sensitive to erythromycin
- 20. Pharmacokinetics • Erythromycin baseis acid labile • To protect it from gastric acid, given as enteric- coated tablets, from which absorption is incomplete and food delays absorption by retarding gastric emptying, its acid-stable esters are better absorbed • Erythromycin is widely distributed in the body, enters cells and abscesses, crosses serous membranes and placenta, but not cross blood- brain barrier
- 21. Adverse effect anddrug interaction Gi disturbance Jaundice Ototoxicity
- 22. Therapeutic Applications ofMacrolides 1. Respiratory tract infections: community-acquired pneumonia (CAP) pharyngitis, sinusitis, bronchitis diphtheria 2. Sexually transmitted infections: chlamydial infections ,chancroid and syphilis 3. Gastrointestinal infections: campylobacter enteritis, helicobacter pylori eradication 4. Pertussis (whooping cough) 5. Prophylaxis in immunocompromised patients: MAC (mycobacterium avium complex) infection in AIDS
- 23. Lincomycin & Clindamycin Classification: •Lincomycin – natural lincosamide (rarely used now) • Clindamycin – semisynthetic derivative of lincomycin (more commonly used) Mechanism of Action: • Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit • Bacteriostatic (can be bactericidal at high concentrations)
- 24. Antibacterial Spectrum: • Goodactivity against Gram-positive cocci (including Streptococci, Staphylococci) • Active against anaerobes – especially Bacteroides fragilis • Not effective against aerobic Gram-negative bacilli
- 25. Therapeutic Uses (mainlyClindamycin): 1.Anaerobic infections – especially intra-abdominal, pelvic, and dental infections 2.Aspiration pneumonia 3.Skin and soft tissue infections by Gram-positive cocci 4.Toxoplasmosis in combination with pyrimethamine 5.Prophylaxis of endocarditis in penicillin-allergic patients undergoing dental procedures 6.Topical use in acne vulgaris (Clindamycin gel/lotion)
- 26. Adverse Effects: • Diarrhoea •Pseudomembranous colitis due to Clostridioides difficile overgrowth • Rashes, liver dysfunction, neutropenia
- 27. Linezolid Classification: • Oxazolidinone classof synthetic antibacterial agents Mechanism of Action: • Inhibits bacterial protein synthesis by binding to 23S rRNA of 50S ribosomal subunit, preventing formation of the initiation complex • Bacteriostatic against most organisms, but bactericidal against Streptococcus pneumoniae
- 28. Spectrum of Activity: •Active against resistant Gram-positive organisms: • MRSA (Methicillin-resistant Staphylococcus aureus) • VRE (Vancomycin-resistant enterococci) • Penicillin-resistant pneumococci • Not effective against Gram-negative bacteria
- 29. Therapeutic Uses: 1.Serious infectionscaused by resistant Gram-positive cocci 1. MRSA infections 2. VRE infections 3. Nosocomial pneumonia 4. Skin and soft tissue infections 2.Off-label use – drug-resistant TB (MDR-TB, XDR-TB)
- 30. Adverse Effects: • Myelosuppression(esp. thrombocytopenia on prolonged use) • Peripheral and optic neuropathy • Lactic acidosis • Serotonin syndrome (with SSRIs/MAOIs – Linezolid is a weak MAO inhibitor)
- 31.