Macrolides

Question 1

Mode of action of macrolides (erythromycin)

Answer 1

Inhibition of protein synthesis, by reversible binding to a component of the large ribosomal sub-unit (50S).
The specific molecular target is bacterial 23S ribosomal RNA

Question 2

What type of binding does erythromycin to ribosomal 50s subunit of

Answer 2

Reversible binding - leads to inhibiting translocation step

Peptidyl tRNA migrate from A to P site

Question 3

Erythromycin functions as a…

Answer 3

Molecular plug (erythromycin:23s rRNA complex) - blocking entrance of the exit tunnel

Question 4

Interactions in erythromycin:23s rRNA complex

Answer 4

H-bonding

Question 5

Pivotal interactions via H-bond in erythromycin

Answer 5

2-OH 5 -sugar with A2058Ec + A2059Ec

6-OH with A2062Ec

Question 6

How does resistance to erythromycin commonly occur

Answer 6

Modification of 23s rRNA
2 mechanisms
- Erythromycin resistance methyltransferases (Erm) mediated mono- and di-methylation of 23S rRNA at the N6 of A2058Ec.
- Mutational alterations of 23S rRNA nucleotides 2057-2059Ec, e.g. A→G2058Ec mutation.

Question 7

Other mechanisms of resistance to erythromycin

Answer 7

Increased drug efflux
O-Glycosylation of the 2’-OH in 5-sugar
O-Phosphorylation of the 2’-OH in 5-sugar