Inhibitors of Ergosterol Biosynthesis as Antifungal Agents

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Abstract
The rise in the incidence of fungal infections over the past two to three decades, particularly those caused by opportunistic pathogens in immune-compromised patients, has strengthened the need for new antifungal drugs. Up to only 30 years ago the choice of systemically available antimycotics was between two drugs, amphotericin B and 5-flurocytosine, neither of which was satisfactory. Then a series of inhibitors of the biosynthesis of ergosterol, the major sterol of the fungal cell membrane, were found to have excellent antifungal activity, improved safety, and some were also active after oral or parenteral application. Starting with miconazole and ketoconazole, and improving through fluconazole and itraconazole, the imidazole and triazole inhibitors of lanosterol Cl4u-demethylation have been the most successful. Other steps in the linear sterol biosynthesis pathway are inhibited by the allylamines naftifine and terbinafine, and the morpholine derivative amorolphine, which have also improved the therapy of superficial mycoses. The discovery, mode of action, current clinical application and future possibilities for these drugs is reviewed. The status and potential of SBI antifungals in development, exclusively azoles, is discussed. Attempts to discover non-azole inhbitors of lanosterol C14u-demethylase are mentioned, as well as current work on other targets in the ergosterol biosynthetic pathway. Particular attention is paid to the oxidsqualene cyclase, which has been extensively studied. The current knowledge about resistance to antifungal agents is reviewed.

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