ANTIFUNGAL DRUGS

Pharmacology of Antifungal Drugs

Challenges in Drug Design

  • Fungal and mammalian cells share similarities, making selective toxicity challenging.

  • The main differences include:

    • Presence of fungal cell walls.

    • Minor structural differences in the plasma membrane.

Fungal Cell Wall

  • Composed of:

    • Mannoproteins.

    • Rigid layers of complex polysaccharides:

      • β-1,3 and β-1,6-linked glucans.

      • Chitin.

  • Functions:

    • Provides mechanical strength.

    • Acts as a barrier, protecting the fungus.

Plasma Membrane

  • Composed of a phospholipid bilayer.

  • Major sterol: Ergosterol (similar to cholesterol in mammalian cells).

  • Contains enzymes responsible for cell wall construction.

Antifungal Drug Targets

  • Ergosterol as a target:

    • Many antifungal drugs target ergosterol due to its key functions.

    • Amphotericin B:

      • Mechanism: Binds to ergosterol, forming pores that allow ion leakage, leading to cell death.

      • Drawback: Can bind to cholesterol, leading to nephrotoxicity.

      • Typically used for severe systemic infections.

    • Nystatin:

      • Similar mechanism to Amphotericin B but more toxic.

      • Used for superficial Candida infections, not systemically absorbed.

Other Antifungal Drug Classifications

  • Squalene Epoxidase Inhibitors:

    • Allylamines (e.g., Naftifine, Terbinafine, Butenafine):

      • Target squalene epoxidase to impair ergosterol synthesis.

  • 14α-Demethylase Inhibitors:

    • Azoles (e.g., Clotrimazole, Fluconazole, Itraconazole, Ketoconazole, Miconazole, Voriconazole):

      • Inhibit 14α-demethylase, depleting ergosterol and leading to toxic sterol accumulation.

      • Potential for adverse effects due to inhibition of human enzymes.

Unique Target: Beta-Glucan

  • Targeting beta-glucan synthesis:

    • Enzyme: β-(1,3)-glucan synthase.

    • Echinocandins:

      • Drugs like Anidulafungin, Caspofungin, and Micafungin inhibit β-glucan synthase.

      • Result: Decreased β-glucan, causing osmotic instability and cell lysis.

      • Advantages: Effective against azole-resistant Candida and Aspergillus species; low toxicity risk.

Additional Antifungal Drugs

  • Griseofulvin:

    • Mechanism: Binds to tubulin, disrupting microtubule function to inhibit cell mitosis.

  • Flucytosine:

    • Mechanism: Converted into 5-fluorouracil; inhibits fungal RNA and DNA synthesis.