Anti-Fungals

Question 1

What are the key sterols in mammalian and fungal cells? What is the difference between them?

Answer 1

mammalian - cholesterol
fungal - ergosterol

ergosterol has

• an extra double bond between C-7 and C-8
• an extra double bond between C-22 and C-23
• an extra methyl group at C-24

Question 2

What is the purpose of sterols?

Answer 2

sterols control the fluidity of the membrane and help to maintain its stability

Question 3

How are cholesterol and ergosterol synthesised?

Answer 3

squalene (precursor) is converted to squalene epoxide by enzyme squalene epoxidase

squalene epoxide is converted to lanosterol by enzyme squalene cyclase

lanosterol can be converted to cholesterol or ergosterol

Question 4

What are the different types of anti-fungals?

Answer 4

allylamines
azoles - imidazoles and triazoles
polyenes
griseofulvin
flucytosine

Question 5

What is the mechanism of action of allyamines?

Answer 5

process involves selective inhibition of the fungal enzyme squalene epoxidase over the mammalian enzyme

• results in a build up of squalene and a lack of ergosterol
  = fungistatic depletion of ergosterol
• compromises the integrity of the cell membrane leading to cell death

Question 6

What is the mechanism of azoles?

Answer 6

both azoles inhibit demethylase enzymes of the cytochrome P450 family in the biosynthetic pathway between lanosterol and ergosterol

inhibit

• 14-alpha demethylase
• 4-alpha demethylase

are either fungistatic or fungicidal dependent on concentration

Question 7

What is the difference between the azoles?

Answer 7

imidazole
- have two nitrogens in the five membered ring

triazole
- have three nitrogens in the five membered ring

Question 8

What is the mechanism of action of polyenes?

Answer 8

polyenes bind to sterols in the cell membrane
- have a higher affinity for ergosterol

polyenes/sterols units form rings making a channel in the cell membrane

• pores are big enough to allow the passage of potassium and magnesium ions out of the cell
• pores alter the membrane structure and activity of membrane associated enzymes

Question 9

What is the mechanism of action of griseofulvin?

Answer 9

mechanism of action is similar to anti-cancer drugs
= vinblastin, paclitaxel

griseofulvin binds to tubulin and prevents the polymerisation of tubulin into microtubules
- inhibition of microtubule formation prevents the formation of the mitotic spindle and hence mitosis causing cell death

Question 10

What is the mechanism of action of flucytosine?

Answer 10

flucytosine is an antimetabolite prodrug

after being taken up into the cell, it undergoes deamination via cytosine deaminate
- forms 5-fluorouracil

5-fluorouracil replaces uracil in the RNA which then inhibits DNA and protein synthesis

mammalian cells lack cytosine deaminase
- selective toxicity