1. Antibacterial Agents: Protein Synthesis Inhibitor Antibiotics
Sachin Shinde
Assistant Professor
S.M.Joshi college, Hadapsar

2. Components of Protein synthesis
1. Protein Synthesis occurs in the ribosomes Eukaryotic cell (mammal) and Prokaryotic cell (bacterial) ribosomes are different, which becomes basis for selective antimicrobial action. 3. Bacterial ribosome (70s) has 50s and 30s subunits while mammalian cell (80s) has 60s and 40s ribosomal subunits. 4. Other components involved are m-RNA which forms template for protein synthesis and t-RNA transfers the individual amino acids to the ribosomes.

3. Review of Protein synthesis in Prokaryotic cell

4. Respective Sites of Action

5. 1. Macrolides Spectrum of activity
Macrolides natural lactones with a large ring, consisting of 14 to 20 atoms.
Ex. Erythromycin
Spectrum of activity
Generally, macrolides are active against gram-positive cocci (staphylococci and streptococci) bacilli, and to lesser-extent gram-negative cocci.
Mode of action and Biological activity
Macrolides bind to the 50S subunit of the bacterial ribosome reversibly, blocks the binding of t RNA to acceptor site and inhibit ribosomal translocation, leading to inhibition of bacterial protein synthesis.
Their action is primarily bacteriostatic.
Why are macrolides NOT very effective against Gram-negative bacteria?
They have large hydrophobic molecules and cannot penetrate both the inner and outer membranes of Gram-negative bacteria.

6. Erythromycin
A 14-member macrocyclic lactone ring to which are attached two sugar moieties,
At C5- desosamine (Amino sugar= Basic character)and C3-cladinose .
Administrated Orally, may be applied topically.
Bitter in taste hence various derivatives were prepared.
Modifications:
At Free OH grp. of Desosamine- acid salts and ester derivatives (Rapid absorption/ higher and prolonged concentration in blood stream).
The stearate is water insoluble and tasteless used as tablet.
Removal of sugars from its structure results in complete loss of activity.
C9-oxime reduces its activity to 10%

7. Clarithromycin Azithromycin (6-O-methyl-erythromycin)
6-position a methoxy group replaces
the hydroxyl group.
No much change in activity.
Azithromycin
A 15-membered ring macrolides,
which differs erythromycin
by the addition of a methyl-substituted
nitrogen atom into the lactone ring.
This improves acid stability and
tissue penetration as well as broadens
the activity spectrum.

9. 2. Chloramphenicol Mechanism of action
Introduced into clinical practice in 1949, under the trade name Chloromycetin.
First antibiotic to be manufactured synthetically on a large scale.
Spectrum: A broad spectrum antibiotic
Useful for the treatment of a meningitis, plague, cholera, and typhoid fever etc.
Mechanism of action
Bacteriostatic
Inhibits the peptide transferase enzyme required for peptide elongation.
It specifically binds 50S ribosomal subunit, preventing peptide bond formation.
Chloramphenicol and the macrolides both interact with ribosomes, but former directly interferes with substrate binding, whereas macrolides sterically block the progression of the growing peptide

10. Biological Activity:
Replacement of the nitro grp. with other substituents like CN, CONH2,SO2NHR,NHR, Cl, Br results in loss of activity.
Methyl thiols and methyl Sulphonyl compounds were promising analogs but had undesirable toxicity.
Shifting NO2 from para position reduces the activity.
Replacement of phenyl moiety by other
aromatic/heterocyclic grp. reduces the activity.
Primary alcohol essential grp. for activity.

11. 3. Amino glycosides
They include the first-in-class amino glycoside antibiotic streptomycin derived from Streptomyces species used in treatment of serious infections.
Ex. Streptomycin, kanamycin, gentamicin, neomycin etc.
- Consist of at least two amino sugars linked by glycoside bonds to an
Amino cyclitol ring
-Highly polar molecules hence do not distribute well in body
-Administration : IM/IV
-Narrow therapeutic index

12. Mode of action and Biological Activity
A bactericidal agent with multiple mechanisms of action. The primary target is the 30S ribosome causing premature chain termination and m RNA codon misreading. In addition causes leakage of the outer membrane of Gram negatives.
Broad spectrum activity
Used in the treatment of infections caused by aerobic G-ve /pseudomonas
Toxicity (Nephro and ototoxicity) is observed which restrict their use.

13. 4. Tetracyclins Medical uses
In the 1950 , when most of the tetracyclins were discovered, their antimicrobial spectrum was broader than that of any other antibiotics then known.
Medical uses
Used in the treatment of infections of the urinary tract, respiratory tract, and the intestines and are used especially in patients allergic to β-lactams and macrolides.

14. How do tetracycline work?
Various family members created by modifying the left 3 rings(R1-R4)
Bacteriostatic broad spectrum antibiotic
Given orally, excellent tissue distribution
Hepatic toxicity observed hence avoided in pregnancy.
How do tetracycline work?
Mechanism of action: They are primarily bacteriostatic.
Inhibit protein synthesis by binding to 30s ribosomal unit which inhibit binding of amino acyl t-RNA to the acceptor site of t- RNA due to which peptide chain fails to grow.

15. Protein Synthesis Inhibitors
Tetracycline
Amino glycosides
Macrolides
Chloramphenicol
Protein Synthesis
Inhibitors

16. Thank you for your kind attention