Anti-fungal drugs

Question 1

What is another name for a fungal disease?

Answer 1

‘mycoses’ - eukaryotes

1. superficial mycoses affect:
   - scalp, nails, skin, mucous membranes (oral cavity and vagina)
   - not life-threatening (opportunistic pathogens)
2. systemic mycoses affect:
   - internal organs (kidneys, lung, brain)
   - fatal in severely immuno-comprimised patients (become opportunistic pathogens)

Question 2

Most common opportunistic pathogens

Answer 2

Candida albicans (commensal)
Aspergillus fumigatus (environmental)
Cryptococcus neoformans (environmental)

Question 3

What puts patients at higher risk of fungal infections?

Answer 3

impaired immune system - 
- HIV/aids
- organ transplantation
- long term course of antibiotics
- premature birth
- cancer
- hospitalisation in ICU
menstrual cycle in women

Question 4

Targets for fungal cell treatment

Answer 4

cell wall - skeletal and matrix components
> skeletal cell wall contains B1-3 Glucan and Chitin
> matrix contains Mannan (protein)
plasma membrane
nucleus (DNA and RNA synthesis)

Question 5

Anti-fungals that inhibit the cell wall

Answer 5

Echinocandins

eg. Caspofungin, Micafungin

Question 6

What are the main differences between human and fungal plasma membranes?

Answer 6

PM’s in fungal cells contain ergosterol, those of human cells contain cholesterol
without ergosterol cells cannot survive and grow

Question 7

What are the 2 types of anti-fungal’s that target ergosterol?

Answer 7

some kill existing cells (bind to resident ergosterol in PM)

others inhibit new cell’s production

Question 8

Polyene antifungals

Answer 8

ergosterol inhibitor
polyenes are fungicidal
bind to engosterol and form pores in the plasma membrane
pores disrupt membrane integrity causing leakage of cell constituents
prolonged application associated with kidney failure
eg. Amphotericin B -
Nystatin - used in treatment of oral and GI fungal infections
both natural in origin

Question 9

Azoles

Answer 9

ergosterol inhibitor
are fungistatic
inhibits the enzyme Lanosterol C-14 demethylase
inhibition of the enzyme:
- blocks ergosterol biosynthesis
- leads to accumilation of toxic intermediates
- causes growth arrest
2 types:
- Imidazoles eg. Miconazole
- Triazoles eg. Fluconazole (more potent as higher affinity for enzyme)

Question 10

Allylamines

Answer 10

ergosterol inhibitor

eg. Terbinafine, Amorolfine

Question 11

RNA & DNA synthesis as targets for antifungals

Answer 11

eg. Flucytosine
- taken up by fungal cells
- metabolised by fungal cells by 5-fluorouracil (5-FU)
- 5-FU is a toxic anti-metabolite that inhibits DNA and RNA synthesis
- usually used in combination with azoles

Question 12

Anti-fungal resistance

Answer 12

caused by:

• decreased accumulation of the drug
• inactivation of the drug
• mutations in drug target-encoding genes
• biofilm formation (grwoth on catheters)