Molecular studies on azole sensitivity in fungi

Abstract

Azole inhibitors of fungal sterol 14α-demethylase have provided a rich source of drugs and pesticides and new compounds are continuing to be evaluated for efficacy. The inhibition of the cytochrome P450 enzyme mediating this reaction was indicated by the effect on ergosterol biosynthesis, with the accumulation of C 14-methylated sterols (figure 1; for review; Vanden Bossche, 1985). Despite their importance many of the molecular details of azole tolerance and resistance are only now beginning to be addressed and revealed. Compounds found to be active as inhibitors of sterol 14α-demethylase include pyrimidines, piparazines, pyridines, imidazoles and triazoles (Kato, 1986). The imidazoles and particularly the triazoles have been successfully developed as orally active drugs (figure 1). Molecular genetic techniques and molecular modelling may assist the design of further drugs. Increased importance for the development of new anti-fungals has resulted from the susceptibility to fungal infections of increasing numbers of immuno-compromised patients. Fungal resistance has also been reported and a molecular understanding is desirable here also.