Antifungal Drugs

Question 1

Explain antifungal drus that target the plasma membrane

Answer 1

• PM in fungal cells contain ergosterol whereas human PM’s contain cholesterol.
• Ergosterol is an essential part of fungal PM - without functional ergosterol biosynthesis - fungal cells cannot survive.
• Antifungals that target ergosterol
• Antifungals that bind to resident ergosterol - Amphotericin B, Nystatin
• Antifungals inhibiting ergosterol biosynthesis- Azoles, Allyamines

Question 2

Explain antifungals that target ergosterol (drugs that target the PM)

Answer 2

• Either bind to resident ergosterol in the PM
• Inhibit different ergosterol biosynthetic enzymes and block biosynthesis or ergosterol

Question 3

Explain antifungals that bind to resident ergosterol

Answer 3

• Polyene Antifungals - fungicidal
• Bind to ergosterol and form pores in the PM
• These pores disrupt membrane integrity causing leakage of cell constituents
• Prolonged application linked to kidney failure.
• Amphotericin B
  
  • Severe side effects with prolonged use
• Nystatin
  
  • oral and GI fungal infections.

Question 4

Explain antifungals inhibiting ergosterol biosynthesis (drugs that target the PM)

Answer 4

• Azoles
  
  • Inhibit enzyme Lanasterol C-14 demethylase ( a key step in ergosterol biosynthesis)
  • Leads to an accumulation of toxic intermediates
  • Causes growth arrest
  • 2 types:
  • Imidazoles - Miconazole, Ketoconazole, Clotrimazole
  • Triazoles - Fluconazole, Variconazole, Itraconazole
• Allylamines
  
  • Inhibit earlier step to ergosterol biosyntesis.
  • Terbinafine
  • Amorolfine

Question 5

Explain antifungals targeting RNA & DNA synthesis

Answer 5

• Flucytosine
• Taken up by fungal cells - metabolised to 5-fluorouracil (5-FU) which is a toxic antimetabolite.
• 5-FU inhibits fungal DNA or RNA
• Associated with high levels of resistance.
• Usually used in combination with azoles

Question 6

Explain resistance to antifungals

Answer 6

• Caused by:
  
  • Decreased accumulation of the drug (increased efflux or decreased permeability to the drug)
  • Inactivation of the drug
  • Mutations in drug target-encoding gene
  • Biofilm formation (growth on plastic surface-catheters)

Question 7

Mycoses are diseases caused by

Answer 7

Fungi

Question 8

In fungi, flucytosine inhibits the biosynthesis of

Answer 8

DNA and RNA