Antifungals

Question 1

What do Echinocandins target?

Answer 1

They are cyclic hexapeptides with N-lined acyl lipid side chains that act via non-competitive inhibition on B-1,3 glucan synthase (FKS1p subunit) to inhibit B-1,3 glucan synthesis, which is an integral part of fungal cell walls.

Question 2

What happens with the use of Echinocandins?

Answer 2

Build a cell wall that is more prone to lysis and death.

Question 3

How are Echinocandins administered?

Answer 3

Poor bioavaliability so have to be given intravenously.

Question 4

What does Nikkomycin Z target?

Answer 4

Chitin synthesis inhibition via competitive inhibition of chitin synthase (another part of the cell wall).

Question 5

What 3 polysaccharides and other proteins make up a fungal cell wall?

Answer 5

Inner layer contains B-1,3 glucan and B-1,6 glucan and chitin, the outer layer containing N- and O- linked mannose proteins.

Question 6

How does nikkomycin Z enter the cells and who is it used on?

Answer 6

Enters cells by a peptide endocytosis, and is only used in vetinary settings as it has not progressed beyond clinical trials as it was too expensive.

Question 7

What is the fungal equivalent to cholesterol?

Answer 7

Ergosterol

Antifungals can target ergosterol itself, or ergosterol production to impact membrane fluidity and functionality.

Question 8

What are the differences between ergosterol and cholesterol?

Answer 8

Cholesterol is signmoidal
Ergosterol is cylindrical

Question 9

What are examples of polyenes?

Answer 9

Amphotericin Bv (IV) and Nystatin (oral)

Question 10

What do polyenes target?

Answer 10

They bind to ergosterol and increase the cell membrane permeability, especially to monovalent cations (e.g. K+) which results in leakage, cell lysis and cell death.

Causes Potassium/proton efflux.

Question 11

Some disadvantages with using amphotericin B?

Answer 11

It is not very water soluble, so has to be used as lipid complexes:
- Multilamellar ribbon-shaped complex
- Small spherical unilamellar liposomes
- Micellar structure

And they are not completely selective, ergosterol packs better, but polyenes have a low affinity for cholesterol so have severe side effects such as shaking, vomiting, fever, anaphylaxis, nephrotoxicity (problems with cells in the liver) and can be potentially lethal.

Question 12

What does reducing ergosterol levels do?

Answer 12

Reducing ergosterol elvels and increasing levels of the intermediates in the biosynthetic pathway leads to toxicity inside the fungal cell.