Antimicrobials

Antifungals

Four major groups of drugs are used to treat fungal infections: polyenes, azoles, echinocandins, and cytosine nucleotide analogs.

Fungal infections are often more difficult to treat than bacterial infections. Humans and fungi are more closely related and share more biochemistry than humans and bacteria. Because of that shared biochemistry, many antimicrobials with potent antifungal activity are also quite toxic to human cells.

One difference between animals and fungi is the structure of the sterol used to maintain fluidity of cell membranes. Polyene antifungal drugs take advantage of this difference. They bind to the fungal sterol in the cell membrane, increasing its rigidity and causing the membrane to leak ions, leading to cell death. Various polyene antifungal drugs are used to treat a wide range of fungal infections, ranging from surface infections of the epidermis to gastrointestinal infections to systemic fungal infections, such as cryptococcal meningitis. Azole antifungals are another group that takes advantage of the sterol used in fungal cell membranes. Instead of directly binding the sterol, they inhibit its synthesis.

There are two groups of azole antifungals: the imidazole group and the triazole group. The imidazole group is widely used in agriculture for preventing the growth of fungi on the roots of crop plants, and for the topical treatment of skin infections such as athlete's foot. The triazole group is administered orally or intravenously for the treatment of yeast infections, such as that caused by Candida sp. This antimicrobial interferes with the barrier functioning of the cell membrane and its associated enzymes.

Fungi and animal cells are also differentiated by the presence of a cell wall around fungal cells. Echinocandin antifungal drugs target an enzyme responsible for the synthesis of a polymer called glucan used in fungal cell walls. Several echinocandins are available for oral or intravenous treatment of local aspergillosis infections or systemic yeast infections. A final group of antifungals takes advantage of fungi-specific enzymes to create cytosine nucleotide analogs in fungal cells. Because the antifungal drugs are not biologically active until conversion, they are able to travel through the human host without causing problems. Once moving into the fungal cell, the drugs are converted by a fungal enzyme to a cytosine analog. The cytosine analog then disrupts DNA and RNA synthesis when it is substituted for cytosine in newly synthesized nucleotide sequences.