Exam 2: Antifungal drugs

Question 1

Fungal Cell

Structure

Answer 1

Question 2

Echinocandins

Answer 2

Targets the cell wall.

• ⊗ synthesis of β-1,3-glucan
  
  • Component of fungal cell wall
• Distrupts cell wall integrity ⇒ osmotic stress/lysis ⇒ death
• Ex. Capsofungin

Question 3

Polyenes

Answer 3

Targets the cell membrane.

• Binds to ergosterol in the cell membrane
  
  • Causes channels or pores
  • ∆ membrane permeability
  • Allows for leakage of cellular contents
  • Leads to cell death
• Main agent in this class is amphotericin B
  
  • Was the main treatment for systemic fungal infections
  • Less used now d/t availability of other broad-spectrum agents

Question 4

Allylamines

Answer 4

Inhibits ergosterol synthesis.

• ⊗ squalene epoxidase
  
  • Catalyzes squalene → lanosterol
    
    • Lanosterol → ergosterol
• Leads to toxic accumulation of squalene
• Ex. Terbinafine

Question 5

Azoles

Answer 5

Inhibits ergosterol synthesis.

• ⊗ 14α-sterol demethylase
  
  • Fungal cytochrome P450 enzyme
  • Normally lanosterol → ergosterol
• Leads to accumulation of 14α-methyl sterols
  
  • Disrupts tightly packed acyl chains of PL in membrane
  • Destabilizes the membrane
  • Causes dysfunction of membrane associated enzymes
• Causes many drug interactions d/t inhibition of CYP450 system
• Ex. Clotrimazole

Question 6

Flucytosine

Answer 6

Inhibits nucleic acid synthesis.

• Anti-metabolite that interferes with DNA synthesis
• Selectively taken up by fungal cells via cytosine specific permeases
  
  • Expressed only on fungal membranes
• Inside cell converted to 5-fluorouracil
  
  • Ultimately converted to metabolite that ⊗ thymidylate synthase
    
    • Disrupts DNA synthesis
• Primarily used in combo with amphotericin for cryptococcal disease