Mechanisms of Action of Antifungal Agents

Fungal and human cells, because of phylogenetic similarities, have homologous metabolic pathways to generate energy, to synthesize proteins, and for cell division. Currently available antifungal agents may be categorized according to their molecular targets. Primary molecular targets for antifungal agents are enzymes and other molecules involved in cell wall synthesis, plasma membrane synthesis, fungal DNA synthesis, and mitosis (Figure 1).5

Figure 1. Molecular Targets for Antifungal Agents.

Unlike human cells, fungal cells are surrounded by a cell wall. Its major components are chitin, Β-(1,3)-D-glucan, Β-(1,6)-D-glucan, and several glycoproteins. Chitins are linear polysaccharides that are bundled into microfibrils and serve as scaffolding for the fungal cell wall. Β-(1,3)-D-glucan and Β-(1,6)-D-glucan are glucan polymers that are covalently linked to the chitin scaffold. The echinocandin antifungal agents are inhibitors of Β-(1,3)-D-glucan synthase.5

Another important biochemical difference between human and fungal cells is related to the sterol used to maintain plasma membrane structure and function. Human cells use cholesterol, whereas fungal cells use the structurally distinct ergosterol. The first step in the biosynthesis of ergosterol involves the conversion of squaline to lanosterol by squaline epoxidase. The allylamine and benzylamine antifungal agents are inhibitors of squaline synthase.5

The second step in plasma membrane synthesis is the conversion of lanosterol to ergosterol. This step is mediated by 14α-sterol demethylase, a fungus-specific cytochrome P450 enzyme. The azole antifungal agents are inhibitors of 14α-sterol demethylase.5 Predictably, the allylamine, benzylamine, and azole antifungal agents sequentially inhibit ergosterol synthesis. The polyene antifungal agents bind to ergosterol and disrupt fungal plasma membrane stability.5

The antifungal agent flucytosine is absorbed via cytosine-specific permiases lacking in human cells. Flucytosine is metabolized to 5-fluorouracil, which is converted to 5-fluorodeoxyuridylic acid monophosphate (5-FdUMP). 5-FdUMP inhibits thymidylate synthase; consequently, it inhibits DNA synthesis and cell division.5 The antifungal agent griseofulvin inhibits microtubule function; consequently, it disrupts the mitotic spindle, and inhibits mitosis.5