FP - Inhibitors of Bacterial Protein Synthesis

Question 1

What are examples of translation 30S subunit inhibitors (2) and translation 50S subunit inhibitors (2)?

Answer 1

Translation (30S subunit) inhibitors

• Aminoglycosides
• Tetracyclines

Translation (50S subunit) inhibitors

• Macrolides
• Chloramphenicol

Question 2

What are 3 features of Aminoglycosides?

Answer 2

e.g. Streptomycin

• First antibiotic to inhibit Gram-negative organisms
• Broad Spectrum (also gentamicin or neomycin)
• Saved millions of lives:
  Nobel Prize for Physiology or Medicine in 1952

Question 3

What is the 2 step mechanism of aminoglycosides?

Answer 3

Binds irreversibly to the 30S subunit on 16S rRNA

1) Freezes protein synthesis initiation

• Accumulation of 70S monosomes in a frozen initiation complex

Important: it does not inhibit elongation.

• In hybrid cell, sensitivity is dominant over resistance

2) Causes misreading of the genetic code

• Destabilizes binding between the subunit and the “correct” tRNA
• Simultaneously stabilize the binding of the subunit to the “wrong” tRNA, thereby effectively removing the discrimination between the correct and the wrong tRNA.

Question 4

What are 3 features related to resistance of streptomyocin?

Answer 4

1. Decrease uptake
2. Altered ribosomes (due to mutations where)
3. Modification of Streptomycin

Question 5

What are 3 side effects caused by aminoglycosides?

Answer 5

• Muscle weakness – decreased release of acetyl choline (binding to Ca2+ sites on the presynaptic membrane)
• Reversible ototoxicity
• Nephrotoxicity

Question 6

How do tetracyclines prevent translation?

Answer 6

Binds to the 16S rRNA

Blocks binding of incoming aminoacyl-tRNA to the A-site

Question 7

What is the site and mechanism of action of tetracyclines? (3)

Answer 7

• The functional group of tetracycline binds to the residues of the 30S ribosomal subunit
• Prevents aminoacyl-tRNA binding
• Tetracyclines interact with magnesium, calcium, etc

Question 8

What are side effects and uses of Tetracyclines? (3)

Answer 8

• Tetracyclines chelate calcium and prevents its absorption, therefore its use leads to calcium deficiency
• Tetracycline drugs such as doxycycline are used for skin infections (treatment of acne); respiratory infections, eye infections, anthrax
• Skin photosensitivity

Question 9

What are 2 features of Chloramphenicol?

Answer 9

• Bacteriostatic (reversible)
• Binds 23S rRNA on 50S subunit

Question 10

What is the mechanism of action of Chloramphenicol? (2)

Answer 10

• Inhibits peptidyl transferase: interferes with peptide bond formation
• Stops protein synthesis: accumulation of polysomes

Question 11

What causes resistance in chloramphenicol?

Answer 11

Chloramphenicol acetyl transferase

Inactivates

Question 12

What are 2 side effects of using chloramphenicol?

Answer 12

1) Grey baby syndrome

• excreted by glucuronidation
• not developed in neonates

2) Reversible anaemia

• bone marrow depression

Question 13

What are 3 types of macrolides?

Answer 13

1. Erythromycin
2. Clarithromycin
3. Azithromycin

Question 14

What are 3 features of macrolides?

Answer 14

1) Most potent against Gram positive bacteria

2) Bacteriostatic (can be cidal in certain cases)

• Inhibit translocation (50S subunit)

3) Used especially for those who cannot take penicillin (for respiratory tract infections)

Question 15

Mechanism of action of macrolides (2)

Answer 15

1. Bind near the peptidyl transferase
2. Inhibit Transpeptidation/Translocation

Question 16

Side effects of macrolides?

Answer 16

Clarithromycin inhibits the cytochrome P450 – especially CYP3A4: its use results in increased serum levels and potential increased toxicities of multiple drugs metabolized by these enzymes