Brian Tenner

1
AntiFungals!

• Brian Tenner
• CHEM 5398
• 22 April 2010

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Outline

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

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Common ancestor?!I am... a mushroom On whom
the dew of heaven drops now and then.-John Ford

• 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! ?)

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Common Fungal Infections!

• Tinea
• Athletes Foot
• Jock Itch
• Ringworm
• Versicolor
• Yeast Infection
• Infection of the Lungs
• Aspergillosis

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Athlete's Foot (Tinea pedis)

• Symptoms scaling, flaking, and itching of the
  feet.
• Caused by Microsporum and Trichophyton
• Treated with various allylamines and azoles,
  miconazole nitrate, and tolnaftate

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Ringworm

• Symptoms Scaling of the skin, characteristic
  circular rash
• Caused by Microsporum and Trichophyton
• Treated with Miconazole, Clotrimazole,
  Ketoconazole

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Tinea Versicolor (?)

• Symptoms Blotches of differing pigmentation
  around upper trunk
• Caused by Malassezia globosa
• Treated with Topical selenium sulfide,
  Clotrimazole, Ciclopirox olamine

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Yeast Infection (Candidiasis)

• Symptoms Localized infection (Thrush),
  inflammation, discomfort
• Caused by Yeast Fungi from genus Candida
• Treated with nystatin, ketoconazole, fluconazole

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Aspergillosis

• Symptoms Delirium, failure of organs, death!
• Caused by Inhalation of fungal spores from
  genus Aspergillus
• Treated with nystatin, ketoconazole,
  fluconazole, capsofungin

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• 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!!

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Common AntiFungals

• 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.

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Amphotericin B (Fungizone)

• Known as a polyene macrolide
• 38 Membered Ring
• Isolated 1955, market 1958
• Amphiphilic!
• Anyone want to guess the Mech Of Action?!?!

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Amphotericin B

• 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??
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Amphotericin b

• Instead of cholesterol in the cell membrane,
  fungal cells have ergosterol. The heptaene
  portion of the ring interacts strongly with
  ergosterol instead of cholesterol.

vs
Ergosterol
Cholesterol
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Fluconazole (Diflucan)

• Bistriazole
• Azole gt 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
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Fluconazole

• 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
  didnt 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).

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Caspofungin (cancidas)

• Semisynthetic cyclic lipid-bearing polypeptide
• Belongs to class of antifungals echinocandins
  derived from
  the cyclic polypeptide.
• Large MW, low oral bioavailability gt
  administered
  intravenously.
• Market 2001

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caspofungin

• 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 fungis cell wall. Human
  cells do not possess a cell wall, so the drug is
  effective.

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Terbinafine (lamisil)

• Belongs to class of antifungals the
  allylamines.
• 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.

Butenafine (Lotrimin)
Terbinafine
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Terbinafine
Terbinafine

• 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.

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References

• 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

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Assigned Reading

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

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Homework

• 1) Why is it so difficult to treat fungal
  infections?
• 2) The target of which biomolecules 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?
•