Mechanisms of Antifungal Drugs

Antifungal drugs suppress or kill fungi by attacking structures or biochemical processes needed for fungal growth. Major classes target the cell membrane, cell wall, nucleic-acid synthesis or mitosis, exploiting differences between fungal and human cells.

Why fungal cells can be targeted

Fungi are eukaryotes, but their membranes contain ergosterol rather than cholesterol as the principal sterol, and their cell walls contain polysaccharides such as beta-1,3-D-glucan. These differences provide selective drug targets, although similarity between fungal and human cells limits the number of safe targets.

Disruption of the cell membrane

• Polyenes, such as amphotericin B and nystatin, bind ergosterol and form membrane channels, causing leakage of cellular contents and cell death.
• Azoles inhibit lanosterol 14-alpha-demethylase, a cytochrome P450 enzyme required for ergosterol synthesis. Ergosterol depletion and abnormal sterol accumulation impair membrane function.
• Allylamines, such as terbinafine, inhibit squalene epoxidase at an earlier step of ergosterol synthesis, causing ergosterol deficiency and toxic squalene accumulation.

Disruption of the cell wall and intracellular processes

• Echinocandins inhibit beta-1,3-D-glucan synthase, weakening the fungal cell wall and producing osmotic instability.
• Flucytosine is converted within susceptible fungi into fluorinated metabolites that inhibit thymidylate synthesis and interfere with RNA, thereby disrupting nucleic-acid production.
• Griseofulvin binds fungal microtubules and disrupts the mitotic spindle, preventing normal cell division.