Antifungal Agents (Timmins)

Question 1

Possible targets for antifungals

Answer 1

1) Cell wall (Echinocandin)
2) Cell membrane (Polyenes and Azoles)
3) DNA Synthesis (5FC)

Question 2

How come you can target the fungal cell membrane without hurting the human cells? (Polyenes)

Answer 2

• Ergosterol (fungi) has 3 double bonds where cholesterol (human) only has one double bond
• This leads to greater selectivity for Ergosterol over cholesterol

Question 3

How do polyenes work?

Answer 3

• They insert themselves into the plasma membranes of fungi
• The inside of these plugs are hydrophilic and allow ions to flow in/out of the cell
• Causing the fungal cell to become leaky and lyse

Question 4

What is/are the resistance mechanisms of polyenes?

Answer 4

-The exact mechanism is unknown

Question 5

Why are polyenes more selective towards ergosterol than cholesterol?

Answer 5

• Because ergosterol has 3x more double bonds

- More double bonds = more Pi Pi stacking

Question 6

What drives polyene specificity

Answer 6

• Also the number of double bonds

- More double bonds = more specific

Question 7

What are the major differences in the formulations of Amphotericin B

Answer 7

• Lipid formulations showed lower toxicity than the Deoxycholate formulation
• Perhaps lower infusion reactions
• Lipid formulations work better in aspergillosis

Question 8

Can you use an in-line filter when giving Abelcet?

Answer 8

• No ya dingus!

- The Abelcet is too big to be able to pass through the filter

Question 9

Which enzyme do Azoles work on

Answer 9

• 14 alpha demethylation

- Safe drug target because there is no close human equivalent

Question 10

How many steps are in 14 alpha demthylation?

Answer 10

• Three successive aliphatic hydroxylations
• Followed by the elimination of formate and water
• All mediated by a heme

Question 11

What components make up an azole

Answer 11

1) Imidazole or triazole pharmacophore (Warhead)
- This binds to the P450 heme site inhibiting it
2) A large and generally hydrophobic R group that mimics lanosterol
- Enhances binding to fungal site and minimizes human p450 binding
3) Usually terminal polarity for solubility

Question 12

Which has higher affinity for the heme in P450? Imidazole or Triazoles?

Answer 12

-Triazole

Question 13

Which Azole works best for treating a fungal infection in nails (toe or finger)

Answer 13

-Jublia (efinaconazole)

Question 14

Which Azole is a prodrug

Answer 14

• Isavuconazonium (Cresemba)
• Polar prodrug of isavuconazole
• The positive charge is delocalized on triazole so it allows for good oral absorption

Question 15

How can fungi develop resistance to azoles?

Answer 15

1) Mutations in gene expression for 14 alpha demethylase
2) Increased efflux pump activity
3) Mutations in other genes

Question 16

What can Terbinafine be used for?

Answer 16

-Treatment of nail fungal infections

Question 17

What is the target of Echinocandins?

Answer 17

• Glucan synthesis
• This makes up part of the cell wall of fungi
• IV only (does not follow the rule of 5s)

Question 18

How does 5FC work?

Answer 18

• 5FC is converted to 5FU (humans lack this enzyme- so its safe)
• 5FU messes up DNA synthase
• Resistance in monotherapy is very rapid