agents that interact with sterols in the microbial plasma membrane. From five to ten
molecules of these antifungals form a conducting pore or channel through which K+
ions, sugars, and proteins are lost from the microorganism. The inside of the pore is
lined with the hydroxyl groups of the macrocyclic molecule; the polyene section inter-
acts with the hydrophobic sterol component of the cell membrane. Because these anti-
fungals interact preferentially with ergosterol, they are fungicidal. With regard to
animal membranes they have a strange selectivity, being lethal to flatworms and snails,
not affecting bacteria, and exerting limited toxicity in mammals. They are used for such
fungal infections as athlete’s foot and vaginal candidiasis, and for systemic (internal)
fungal infections, which are nearly always fatal if untreated. Thus the therapeutic value
of amphotericin B outweighs the drawback of its toxic side effects.
The more recently discovered group of azole antifungal agents also act through
membrane destabilization by inhibiting ergosterol biosynthesis, via 14α-demethylase
enzyme inhibition; the basic nitrogen of the azole forms a bond to the heme iron in the
enzyme, preventing the enzyme from oxidizing its normal substrates. Ketoconazole
(9.105) can be taken orally, whereas clotrimazole (9.106), miconazole (9.107), and
related compounds are applied topically. Other azoles include itraconazole (9.108) and
fluconazole (9.109). The azoles bind very avidly to skin and accumulate in fungi very
rapidly. Although contact times may be only 15–20 minutes, the azole remains in the
fungus for 120 hours and thus, even in sublethal doses, leads to a decrease in virulence.
Another group of sterol synthesis inhibitors (via squalene epoxidase enzyme inhibition)
includes the allylamines, represented by naftifine (9.110) and terbinafine (9.111).
EXOGENOUS PATHOGENS AND TOXINS 583