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The incidence of triazole-resistantAspergillus infections is increasing worldwide, often mediated through mutations in the CYP51A amino acid sequence. New classes of azole-based drugs are required to combat the increasing resistance to existing triazole therapeutics. In this study, a CYP51 reconstitution assay is described consisting of eburicol, purified recombinantAspergillus fumigatus CPR1 (AfCPR1), andEscherichia coli membrane suspensions containing recombinantA. fumigatus CYP51 proteins, allowingin vitro screening of azole antifungals. Azole-CYP51 studies determining the 50% inhibitory concentration (IC50 ) showed thatA. fumigatus CYP51B (Af51B IC50 , 0.50 μM) was 34-fold more susceptible to inhibition by fluconazole thanA. fumigatus CYP51A (Af51A IC50 , 17 μM) and that Af51A and Af51B were equally susceptible to inhibition by voriconazole, itraconazole, and posaconazole (IC50 s of 0.16 to 0.38 μM). Af51A-G54W and Af51A-M220K enzymes were 11- and 15-fold less susceptible to inhibition by itraconazole and 30- and 8-fold less susceptible to inhibition by posaconazole than wild-type Af51A, confirming the azole-resistant phenotype of these two Af51A mutations. Susceptibility to voriconazole of Af51A-G54W and Af51A-M220K was only marginally lower than that of wild-type Af51A. Susceptibility of Af51A-L98H to inhibition by voriconazole, itraconazole, and posaconazole was only marginally lower (less than 2-fold) than that of wild-type Af51A. However, Af51A-L98H retained 5 to 8% residual activity in the presence of 32 μM triazole, which could confer azole resistance inA. fumigatus strains that harbor the Af51A-L98H mutation. The AfCPR1/Af51 assay system demonstrated the biochemical basis for the increased azole resistance ofA. fumigatus strains harboring G54W, L98H, and M220K Af51A point mutations.

In Vitro Biochemical Study of CYP51-Mediated Azole Resistance in Aspergillus fumigatus