Ergosterol Synthesis Inhibitors

Ergosterol is the major sterol of the fungal membrane, and fungi build it through a late pathway whose reactions occur mainly in the endoplasmic reticulum membrane. Two enzymes of that pathway are drug targets: squalene epoxidase (ERG1), which catalyses the epoxidation of squalene to 2,3-epoxysqualene and is potently inhibited by the allylamines naftifine and SF 86-327 (terbinafine), and lanosterol 14-alpha-demethylase (ERG11, also known as CYP51), which catalyses the three-step oxidative removal of the 14-alpha-methyl group of lanosterol and eburicol and is inhibited by the azoles clotrimazole, miconazole, fluconazole and ketoconazole. Drugs acting at either enzyme stop ergosterol synthesis at that step. The class as MED-RT populates it is wider than its name: alongside the azoles and allylamines it holds the polyenes amphotericin B, nystatin and natamycin, which inhibit no enzyme of the pathway - the FDA-approved label for nystatin states that it acts by binding to sterols in the cell membrane of susceptible Candida species, with a resultant change in membrane permeability allowing leakage of intracellular components. For the polyene members the class name is a misnomer: they bind the ergosterol that has already been made.