Antifungal Drugs

Both ergosterol and cholesterol synthesis go from squalene to lanosterol to zymosterol, which is their final common precursor.

Amphotericin B

• 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
Azoles

• Block lanosterol  ergosterol by inhibiting 14-α-demethylase.  Cell membranes increase in permeability.
• Side effects: include severe hepatotoxicity.

Ketoconazole
Orally available, degraded in the liver.  Good alternative to Amphotericin B.

Fluconazole

• 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

Allylamines:
These block an earlier step in ergosterol synthesis (squalene  lanosterol), but doesn’t seem to have any effect on cholesterol synthesis.

Flucytosine (5FC):

• 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.

Griseofulvin: 

• 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.

Caspofungin

• Blocks formation of glucan polymers, so cell walls cannot form.
• Broad spectrum, very high specificity.
• Fights invasive Aspergillus and Candidiasis infections.