Summary
Highlights
Designing antifungal drugs is challenging due to the similarity between fungal and mammalian cells. Key differences exploited are the fungal cell wall and the unique sterol, ergosterol, in the plasma membrane. The fungal cell wall provides structural strength and protection, while ergosterol maintains membrane integrity, similar to cholesterol in human cells.
Ergosterol is a primary target for many antifungal medications. Amphotericin B binds to ergosterol, forming pores that cause leakage of intracellular ions and fungal cell death. However, it can also bind to cholesterol in human cells, causing nephrotoxicity, thus it's reserved for severe systemic infections. Nystatin has a similar mechanism but is more toxic and not used systemically, limited to superficial Candida infections.
Many antifungals target enzymes involved in ergosterol biosynthesis. Squalene epoxidase, which converts squalene to lanosterol, is targeted by allylamines (e.g., Naftifine, Terbinafine). 14α-demethylase, which converts lanosterol to ergosterol, is targeted by azoles (e.g., Clotrimazole, Fluconazole). Inhibiting these enzymes depletes ergosterol, impairing membrane fluidity and causing fungal cell death. However, these enzymes are also present in human cells, leading to potential adverse effects and drug interactions, particularly with azoles and human cytochrome P450 enzymes.
Beta-glucan, a unique component of the fungal cell wall, is another attractive pharmacological target. Echinocandins (e.g., Anidulafungin, Caspofungin, Micafungin) inhibit β-(1,3)-glucan synthase, leading to a decrease in β-glucans and fungal cell lysis due to osmotic instability. A major advantage of echinocandins is their activity against azole-resistant strains and Aspergillus species, with lower toxicity and drug interactions because human cells lack beta-glucan synthesis.
Griseofulvin and Flucytosine disrupt fungal cell division. Griseofulvin binds to tubulin, inhibiting microtubule function and fungal cell mitosis. Flucytosine is converted into 5-fluorouracil, which inhibits fungal RNA and DNA synthesis.