Brian TennerCHEM 539822 April 2010

Early Beginnings – Difficulties Treating Common Fungal Infections Antifungal Drugs Newer Therapies Assigned Reading/References/Homework

About 1408 Million Years Ago, fungi and animals phyla split

We are more closely related to fungi then plants!

This will prove difficult for one to treat mycotic infections due to the similarities between the eukaryotic fungus and the eukaryotic host (us! )

Tinea – Athlete’s Foot Jock Itch Ringworm Versicolor

Yeast Infection Infection of the Lungs

Aspergillosis

Symptoms: scaling, flaking, and itching of the feet.

Caused by: Microsporum and Trichophyton

Treated with: various allylamines and azoles, miconazole nitrate, and tolnaftate

Symptoms: Scaling of the skin, characteristic circular rash

Caused by: Microsporum and Trichophyton

Treated with: Miconazole, Clotrimazole, Ketoconazole

Symptoms: Blotches of differing pigmentation around upper trunk

Caused by: Malassezia globosa

Treated with: Topical selenium sulfide, Clotrimazole, Ciclopirox olamine

Symptoms: Localized infection (Thrush), inflammation, discomfort

Caused by: Yeast Fungi from genus Candida

Treated with: nystatin, ketoconazole, fluconazole

Symptoms: Delirium, failure of organs, death!

Caused by: Inhalation of fungal spores from genus Aspergillus

Treated with: nystatin, ketoconazole, fluconazole, capsofungin

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!!

Amphotericin B Fluconazole Capsofungin Terbinafine

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.

Known as a polyene macrolide 38 – Membered Ring

Isolated 1955, market 1958 Amphiphilic!

Anyone want to guess the Mech Of Action?!?!

Mech of Action!

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.

Cholesterol Ergosterol

vs

Bistriazole Azole => Conjugated five-membered ring with at least 1 N and other

non carbon atoms (could be N) Belongs to a larger class of well known antifungals – imidazoles

(Clotrimazole, Miconazole) Fluconazole is newer though! Imidazoles synthesized to treat both superficial AND systematic infections.

Fluconazole Clotrimazole Miconazole

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.

Market 2001

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.

Belongs to class of antifungals – the al lylamines. Treats mainly superficial infections. Discovered by accident in 1974 - antifungal potential related

directly to the tertiary allylamine and the 1-substituted naphthalene ring. Eventually developed terbinafine.

Terbinafine

Butenafine (Lotrimin)

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. *****

Terbinafine

Molecules and Medicine. EJ Corey. John Wiley and Sons: 2007

Recent Advances in the Chemistry of Anti-Infective Agents. Editors PH Bentley and R. Ponsford. Royal Society of Chemistry: 1993.

http://www.doctorfungus.org. DoctorFungus Corporation

http://faculty.swosu.edu/scott.long/phcl/antifung.htm. Long, Scott, Southwestern Oklahoma State University

Mathew, Bijoy P.; Nath, Mahendra. Recent approaches to antifungal therapy for invasive mycoses. ChemMedChem (2009), 4(3), 310-323.

1) Why is it so difficult to treat fungal infections? 2) The target of which biomolecule’s synthesis is the subject of many antifungal

drugs? 3)     What are the main families of antifungal agents?  Name a member of each

family. 4)       What is the most commonly employed antifungal agent to treat invasive fungal

infections?  Describe its mechanism of action.  What is the major side effect of this agent?

5)     What enzyme is the biological target of the azole antifungal agents?  What is the most common mechanism of fungal resistance to these agents?

6)     The echinocandin caspofungin was approved by the FDA in 2001 for salvage therapy in cases of resistant invasive aspergillosis.  What is the most likely target of these drugs?

7)     Another class of antifungal agents is the allylamines, including terbinafine.  Draw the structure of terbinafine and define the allylamine moiety.  What is the biological target of allylamines?