Both ergosterol and cholesterol synthesis go from squalene to lanosterol to zymosterol, which is their final common precursor.
- This has a special hydrophobic polyene unit that binds ergosterol in the membrane. Forms pores. Selectivity is poor – Amphotericin B also binds cholesterol.
- Toxicity is Shake ‘n’ Bake.
- Used against deep fungal infections like invasive Aspergillosis or disseminated Candidiasis.
Nystatin is a topical preparation of Amphotericin B that treats cutaneous/mucosal Candidiasis.
It is often referred to as “swish and swallow.”
DRUGS THAT INTERFERE WITH ERGOSTEROL SYNTHESIS
- Block lanosterol ergosterol by inhibiting 14-α-demethylase. Cell membranes increase in permeability.
- Side effects: include severe hepatotoxicity.
Orally available, degraded in the liver. Good alternative to Amphotericin B.
- Good penetration into CSF and the eye. Half-life of two days.
- This fungicide will kill Cryptococcus and prevent Candida infections.
- Often used in HIV-positive patients
These block an earlier step in ergosterol synthesis (squalene lanosterol), but doesn’t seem to have any effect on cholesterol synthesis.
- 5FC is converted to 5-FU, so it is a uracil analog. It is converted either to 5-FUMP which is incorporated into fungal mRNA, or to 5-F-dUMP which inhibits thymidylate synthase.
- *This is an excellent example of selective toxicity, because our cytosine deaminase can’t convert it to 5-FU but fungi can! Toxicity may arise by metabolism of 5FC to 5-FU by normal GI flora.
- Resistance is common, so it is used with Amphotericin B.
- Treats Candida and Cryptococcus.
- Disrupts all microtubules, but it’s only actively transported into fungal cells, so that’s the selective toxicity.
- Unique distribution to keratin, so it is used to treat hair/nail/skin infections.
- Blocks formation of glucan polymers, so cell walls cannot form.
- Broad spectrum, very high specificity.
- Fights invasive Aspergillus and Candidiasis infections.