Anti-fungals

Question 1

Fluorine analogue of cytosine (pyrimidine), which inhibits DNA synthesis by inhibiting thymidylate synthetase.
Also converted into 5-fluorouracil, which is incorporated into fungal RNA.

Inhibits ergosterol synthesis by inhibiting the P450-dependent enzyme 14-alpha-demethylase (P45014DM), increasing the cell membrane permeability and eventually causing the cell to lyse.

Answer 1

Flucytosine - Fluorine analogue of cytosine (pyrimidine), which inhibits DNA synthesis by inhibiting thymidylate synthetase.
Also converted into 5-fluorouracil, which is incorporated into fungal RNA.

Imidazoles and triazoles - Inhibits ergosterol synthesis by inhibiting the P450-dependent enzyme 14-alpha-demethylase (P45014DM), increasing the cell membrane permeability and eventually causing the cell to lyse.

Question 2

Inhibits squalene conversion to lanosterol (precursor to ergosterol) by inhibiting the enzyme squalene epoxidase.
Squalene build up in the cell also leads to disruption of cell membrane and keratin deposition.

Bind to ergosterol in the cell membrane and increase the membrane’s permeability. Important cytoplasmic constituents leak out.

Answer 2

Terbinafine - Inhibits squalene conversion to lanosterol (precursor to ergosterol) by inhibiting the enzyme squalene epoxidase.
Squalene build up in the cell also leads to disruption of cell membrane and keratin deposition.

Polyenes - Bind to ergosterol in the cell membrane and increase the membrane’s permeability. Important cytoplasmic constituents leak out.

Question 3

Inhibits P45014DM to a greater extent than other drugs, making it fungicidal against Aspergillus spp.

Disrupts fungal cellular microtubules.

Answer 3

Vorinconazole - Inhibits P45014DM to a greater extent than other drugs, making it fungicidal against Aspergillus spp.

Griseofulvin - Disrupts fungal cellular microtubules.

Question 4

Inhibit glucan synthesis by inhibiting the beta-1,3-D-glucan synthase enzyme complex.
Beta-glucans comprise <60% of yeast cell wall, so these drugs are rapidly fungicidal for yeasts. Beta-glucans in moulds are concentrated at the ends of filaments, so merely fungistatic for Aspergillus.

Answer 4

Echinocandins - Inhibit glucan synthesis by inhibiting the beta-1,3-D-glucan synthase enzyme complex.
Beta-glucans comprise <60% of yeast cell wall, so these drugs are rapidly fungicidal for yeasts. Beta-glucans in moulds are concentrated at the ends of filaments, so merely fungistatic for Aspergillus.

Question 5

Why are fungi such as candida difficult to culture in blood?

Answer 5

They attach/ invade endothelial cells, so unlikely to be free in blood stream

Question 6

What is treatment for these infections

Candida albicans
Candida glabrata
Candida Krusei

Answer 6

Candida albicans - fluconazole. Usually sensitive to most anti-fungals

Candida glabrata + Candida Krusei - resistant to azoles.
Use echinocandin first line, and amphotericin second line (some resistant to amphotericin)

Question 7

Name a drug example for each class:

Polyene
Heterocyclic benzofuran
Echinocandins
Antimetabolite
Imidazole
Triazole
Allyamine

Answer 7

Ergosterol target - forms pores in wall
- Polyene - Amphotericin, nystatin

Ergosterol synthesis inhibitors:

• Imidazole - ketoconazole, miconazole
• Triazole - fluconazole, voriconazole
• Allyamine - terbinafine

Ergosterol synthesis inhibitor - Beta-D-glucan target:
- Echinocandins - caspofungin

Microtubules:
-Heterocyclic benzofuran - griseofulvin

DNA:
- Antimetabolite - flucytosine