Aspergillus fumigatus CYP51 sequence: potential basis for fluconazole resistance.

We have cloned and sequenced the Aspergillus fumigatus CYP51 gene which encodes the target of azole antifungal agents, namely cytochrome P450 sterol 14alpha-demethylase. Since A. fumigatus is intrinsically resistant to the widely used azole fluconazole, we compared its predicted CYP51 sequence to the CYP51 sequences from fluconazole-susceptible and resistant Candida albicans. This analysis generated specific hypotheses regarding the basis for A. fumigatus fluconazole resistance; in particular, A. fumigatus residue Ile301 corresponds to C. albicans residue Thr315 which is mutated to Ala in resistant strains and is proposed to hydrogen bond with the sterol substrate.