INHIBITORS OF PROTEIN SYNTHESIS II Flashcards
Is Erythromycin a natural product or a synthetic product?
It is natural - produced by Soccharopolyspora erythraea (bacteria found in soil)
What’s the structure of Erythromycin A? (3)
- 18 chiral centres
- Alternating oxygen pattern - oxygen on every 2nd carbon in the ring
- Based on a propionate (three carbon unit), so has methyl groups sticking out
In what way are the structures of erythromycin and tetracycline similar?
They are both polyketide - have an alternating oxygen pattern
What type of gram bacteria is macrolides most active against?
Gram Positive bacteria
What are macrolides used to treat?
Deep-seated infections such as TB and Legionnaire’s Disease.
If someone is allergic to penicillins, what is the first line treatment for them?
Macrolides
What enzyme metabolises erythromycin and what can this result in?
- Metabolised by cytochrome P450 3A4
- Drug interactions (leads to overdose if a drug is metabolised by CYP3A4)
What happens when macrolides are taken with food and why?
- Can experience nausea, vomiting, diarrhoea
- Macrolides are gut motility agonists
What is the difficulty of using macrolides in paediatric preparations?
They have a bitter taste which is not easily masked
What is the mode of action of erythromycin?
- Inhibits protein synthesis
- Erythromycin blocks the exit tunnel and not allowing the peptide elongation of the bacterial ribosome
How is the taste of Erythromycin masked?
- Can be given as erythromycin ethyl succinate
- Esters of erythromycin don’t have a taste
- It is a pro-drug (so has no activity itself)
- BUT IT WILL ALSO HYDROLYSE IN THE MEDICINE BOTTLE (this strongly affects the taste)
What is the difference between first and second generation macrolides?
- 2nd generation macrolides are much more stable to acid than erythromycin A (better in stomach)
- 2nd generation macrolides are more hydrophobic
- 2nd generation macrolides have generally favourable pharmacokinetics
What are examples of second generation macrolides?
- Clarithromycin (extra methyl group)
- Azythromycin (missing ketone)
How does Clarithromycin differ from erythromycin A and its effects?
- Clarythromycin has an extra methyl group
- This makes it more hydrophobic
- This is beneficial to the pharmacokinetics
What type of Gram bacteria is Azithromycin most active against?
Gram Negative (+ has some mild anti-malarial activity)
What’s the duration of course for Azithromycin and how does this compare to Erythromycin?
- Azithromycin is a 3 day course (OD)
- Erythromycin is a 7 day course (BD)
What type of Gram bacteria is Clarithromycin active against?
ONLY ACTIVE AGAINST GRAM POSITIVE BACTERIA (better than Erythromycin and Azithromycin)
How long is the half life of Erythromycin A at 37oC and pH 2.5?
Less than 10 minutes
How long is the half life of Clarithromycin at 37oC and pH 2.5?
310 minutes
Give an example of a ketolide
Telithromycin
How have bacteria developed resistance to macrolides? (3)
- Are ketolides affected by this mode of resistance?
- Modification of L22 protein (exit tunnel structure)
- Macrolide efflux pumps
- Methylation of adenine 2058 in 23S RNA (tunnel is made bigger = macrolide cannot block it)
- Ketolides aren’t affected (even though they bind at the same site on the ribosome)
What is convergent synthesis?
The final compound is assembled from pre-assembled compounds
Chloramphenicol is only used to treat gram positive bacteria. True or false?
False - gram positive and gram negative
How many chiral centres does chloramphenicol have?
2 - but only ONE stereoisomer is active
