Which of the following antifungal medications do NOT involve ergosterol as their main MOA?

• A. Ketoconazole
• B. Griseofulvin
• C. Fluconazole
• D. Natamycin

Answer: (B)

Ergosterol is a key component of fungal cell membranes and many antifungals exploit that by either inhibiting its synthesis or binding to it to disrupt the membrane. Azoles, like ketoconazole and fluconazole, block the enzyme that converts sterol precursors into ergosterol, so they reduce ergosterol production. Natamycin, a polyene, doesn’t just reduce ergosterol—it binds to ergosterol in the membrane and forms pores, directly disturbing membrane integrity. Griseofulvin, however, works differently: it binds to fungal microtubules and disrupts mitosis, impairing cell division without involving ergosterol pathways. So the antifungal whose main mechanism does not involve ergosterol is griseofulvin.