Brian Tenner CHEM 5398 22 April 2010. AntiFungals !. Early Beginnings – Difficulties Treating Common Fungal Infections Antifungal Drugs Newer Therapies Assigned Reading/References/Homework. Outline.
22 April 2010
Early Beginnings – Difficulties Treating
Common Fungal Infections
Many of the common fungal infections described affect the general population. There is a vaster majority of fungi that cause serious harm to people that are immunocompromised!!
Keep in mind: We need to target differences between our cell and the fungal cell. Antibiotics will not work because of both cells are eukaryotic and the medication could kill off the good gut flora that competes with the fungus for nutrients. Treatments usually include many combinations of different antifungals.
Associates with the membrane and causes leakage of Na, K, and Ca across membrane. But how does it differentiate between fungal cells and human cells??
Instead of cholesterol in the cell membrane, fungal cells have ergosterol. The heptaene portion of the ring interacts strongly with ergosterol instead of cholesterol.
Mech of Action:
Specifically inhibits the cytochrome P450 fungal enzyme C-14(alpha) demethylase. This enzyme is require in the 20 step pathway [thank goodness we didn’t have to memorize this] from lanosterol (intermediate in cholesterol synthesis) to ergosterol. Fluconazole binds to the Fe center of the enzyme (one of the nitrogens coordinates to the Fe).
Semisynthetic cyclic lipid-bearing polypeptide
Belongs to class of antifungals: echinocandins – derived from the cyclic polypeptide.
Large MW, low oral bioavailability => administered intravenously.
Mech of Action:
Potent inhibitor of the fungal enzyme 1,3-(beta)-D glucan synthase. This enzyme catalyzes glucan polymerization (glucan is just a polymeric sugar molecule), which is essential in the synthesis of a fungi’s cell wall. Human cells do not possess a cell wall, so the drug is effective.
Mech of Action: All allylamines work similarly. They inhibit ergosterol synthesis by inhibiting squalene epoxidase (oh snap!), the enzyme that catalyzes the epoxide formation between the 2 and 3 carbon of squalene. From this 2,3-oxidosqualene intermediate, we produce lanosterol and eventually ergosterol. *****