INHIBITORS OF PROTEIN SYNTHESIS II

Question 1

Is Erythromycin a natural product or a synthetic product?

Answer 1

It is natural - produced by Soccharopolyspora erythraea (bacteria found in soil)

Question 2

What’s the structure of Erythromycin A? (3)

Answer 2

• 18 chiral centres
• Alternating oxygen pattern - oxygen on every 2^nd carbon in the ring
• Based on a propionate (three carbon unit), so has methyl groups sticking out

Question 3

In what way are the structures of erythromycin and tetracycline similar?

Answer 3

They are both polyketide - have an alternating oxygen pattern

Question 4

What type of gram bacteria is macrolides most active against?

Answer 4

Gram Positive bacteria

Question 5

What are macrolides used to treat?

Answer 5

Deep-seated infections such as TB and Legionnaire’s Disease.

Question 6

If someone is allergic to penicillins, what is the first line treatment for them?

Answer 6

Macrolides

Question 7

What enzyme metabolises erythromycin and what can this result in?

Answer 7

• Metabolised by cytochrome P450 3A4
• Drug interactions (leads to overdose if a drug is metabolised by CYP3A4)

Question 8

What happens when macrolides are taken with food and why?

Answer 8

• Can experience nausea, vomiting, diarrhoea
• Macrolides are gut motility agonists

Question 9

What is the difficulty of using macrolides in paediatric preparations?

Answer 9

They have a bitter taste which is not easily masked

Question 10

What is the mode of action of erythromycin?

Answer 10

• Inhibits protein synthesis
• Erythromycin blocks the exit tunnel and not allowing the peptide elongation of the bacterial ribosome

Question 11

How is the taste of Erythromycin masked?

Answer 11

• 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)

Question 12

What is the difference between first and second generation macrolides?

Answer 12

• 2^nd generation macrolides are much more stable to acid than erythromycin A (better in stomach)
• 2^nd generation macrolides are more hydrophobic
• 2^nd generation macrolides have generally favourable pharmacokinetics

Question 13

What are examples of second generation macrolides?

Answer 13

• Clarithromycin (extra methyl group)
• Azythromycin (missing ketone)

Question 14

How does Clarithromycin differ from erythromycin A and its effects?

Answer 14

• Clarythromycin has an extra methyl group
• This makes it more hydrophobic
• This is beneficial to the pharmacokinetics

Question 15

What type of Gram bacteria is Azithromycin most active against?

Answer 15

Gram Negative (+ has some mild anti-malarial activity)

Question 16

What’s the duration of course for Azithromycin and how does this compare to Erythromycin?

Answer 16

• Azithromycin is a 3 day course (OD)
• Erythromycin is a 7 day course (BD)

Question 17

What type of Gram bacteria is Clarithromycin active against?

Answer 17

ONLY ACTIVE AGAINST GRAM POSITIVE BACTERIA (better than Erythromycin and Azithromycin)

Question 18

How long is the half life of Erythromycin A at 37^oC and pH 2.5?

Answer 18

Less than 10 minutes

Question 19

How long is the half life of Clarithromycin at 37^oC and pH 2.5?

Answer 19

310 minutes

Question 20

Give an example of a ketolide

Answer 20

Telithromycin

Question 21

How have bacteria developed resistance to macrolides? (3)

• Are ketolides affected by this mode of resistance?

Answer 21

1. Modification of L22 protein (exit tunnel structure)
2. Macrolide efflux pumps
3. 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)

Question 22

What is convergent synthesis?

Answer 22

The final compound is assembled from pre-assembled compounds

Question 23

Chloramphenicol is only used to treat gram positive bacteria. True or false?

Answer 23

False - gram positive and gram negative

Question 24

How many chiral centres does chloramphenicol have?

Answer 24

2 - but only ONE stereoisomer is active

Question 25

Why is chloramphenicol not usually given internally and how is it mainly given?

Answer 25

• Because it can cause aplastic anaemia.
• It is typically found in eye drops

Question 26

Give some examples of lincosamides? And state if they are natural, semi-synthetic or synthetic?

Answer 26

• Lincomycin - natural product
• Clindamycin - semi - synthetic

Question 27

How is resistance to lincomycin and clindamycin induced?

Answer 27

Methylation of adenine 2058 in 23S RNA

Question 28

What can clindamycin be used for?

Answer 28

• Anaerobic and certain aerobic infections (respiratory tract infections)
• TSS treatment, in combination with vancomycin
• Treatment of protozoa infections (in combination with chloroquine/quinine

Question 29

Fusidic acid is a fungal product. True or false?

Answer 29

True

Question 30

What type of gram bacteria is Fusidic acid most active against?

Answer 30

Gram +ve infections (including mycobacteria), however, it use for M. tuberculosis is disputed

Question 31

What pharmaceutical form can fusidic acid be given as?

Answer 31

Eye drops, tablets or creams (impetigo)

Question 32

What is the mode of action of fusidic acid?

Answer 32

• Binds an EGF-GTP complex which then binds a ribosome
• GTP is hydrolyzed
• The hydrolysis of GTP then prevents the complex (EFG - GDP) from leaving ribosome so protein synthesis is inhibited

Question 33

Name the structure

Answer 33

Lincosamides

Question 34

Name the structure

Answer 34

Fusidic acid

Question 35

Name the structure

Answer 35

Macrolides

Question 36

Name the structure

Answer 36

Chloramphenicol