Antifungals Flashcards
What is dermatophytes more commonly known as?
Ring worm
Give an example of a secondary opportunistic fungal infection
Malassezia spp.
Give an examples of a fungal upper respiratory infection
Aspergillus
List some of the challenges of anti fungal therapy
- Low susceptibility/ resistance (hard to tell which it is)
- Drugs can be slow to take effect because of the slow growing nature of fungus
- Environmental contamination (spores) so fomites leading to reinfection/ cross contamination
- Lack of vaccines
List some unique fungal drug targets
- Chitin cell wall
- Glycan combinations in cell wall
- Main sterol is Ergosterol
What are the main differences between a fungal cell and an animal cell?
- Main sterol in fungus= ergosterol but in animals= cholesterol
- Range of glycans present in fungal cell wall is different to in a eukaryotic cell
What is an antifungal drug that disrupts the membrane of the fungal cell?
Polyenes e.g. Nystatin/ Amphotericin B
- Preferentially bind to ergosterol
- Cause membrane leakage and loss of membrane function (homeostatic problems)
- Can cause toxic side effects as can bind to host membranes
Which groups of antifungals disrupt the ergosterol pathway?
- Azoles and Allylamines
- Can use statins but these have side effects (interfere with cholesterol)
Which part of the Ergosterol pathway do Azoles interupt?
- They inhibit ERG11 (lanostero C-34 demethlase) which leads to an accumulation of toxic methyl-ergostadiene-diol
Which part of the Ergosterol pathway do Allynines disrupt?
They inhibit ERG 1 (squalene epoxidase) leading to an accumulation of Squalene which is toxic
Describe Azoles
- Cause an abundance of toxic methyl-ergostadiene-diol due to inhibiting 14-alpha-dimethylase
- High levels of azoles are toxic
- Fungistatic action
- 2 main groups (imidazoles and triazoles)
- Effective against lots of different fungi e.g. Dimorphic and Dermatophytes BUT doesn’t work on Aspergillus spp.
Describe Allylamines
- Inhibit squalene epoxidase
- Results in reduction of ergosterol production and accumulation of squalene (which is toxic)
- Has broad spec activity
- Very effective against dermatophytes
What is the target of Echincandins?
The chitin/ glycan synthesis in the cell wall
Describe Echinocandins
- Inhibit 1-3 glucan synthase by non-competitive inhibition
- Fungicidal and non toxic
- Depletion of glucan weakens the cell wall
- Only effective is fungus is actively growing as has to have access to hyphae at growing tips and branching point (if no osmotic action or the cell wall is already formed and cell is pretty inert they won’t wokr)
- Can have intrinsic resistance if different glycans e.g. Crytoccocus spp are resistant to it
Discuss antifungals that inhibit nucleus acid and are anti mitotic
(FLUCYTOSINE)
- Flucytosine: only given orally, deaminated in the fungal cell sby an enzymes (cytochrome deaminase) which is not present in animal cells. This forms 2 products FdUMP/ FURTP
- FURTP incorporated in to fungal RNA and inhibits protein synthesis
- FdUMP inhibits DNA synthesis
- Resistance can occur so often used in combination with amphotericin B
