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Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens

Warrilow, Andrew G.S., Parker, Josie E., Price, Claire L., Rolley, Nicola J., Nes, W. David, Kelly, Diane E. and Kelly, Steven L. 2019. Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens. International Journal of Antimicrobial Agents 54 (4) , pp. 449-455. 10.1016/j.ijantimicag.2019.07.011

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Here we report the first evaluation of isavuconazole inhibition of Aspergillus fumigatus CYP51 and thus sterol biosynthesis in the fungus. Voriconazole and isavuconazole both bound tightly to recombinant A. fumigatus CYP51 isoenzymes A and B (AfCYP51A and AfCYP51B) isolated in Escherichia coli membranes. CYP51 reconstitution assays confirmed that AfCYP51A and AfCYP51B as well as three AfCYP51A mutants known to confer azole resistance (G54W, L98H and M220K) were strongly inhibited by both triazoles. Voriconazole bound relatively weakly to purified Homo sapiens CYP51 (HsCYP51), unlike isavuconazole that bound tightly. However, isavuconazole was a relatively poor inhibitor of HsCYP51 activity, with an IC50 value (half-maximal inhibitory concentration) of 25 µM, which was 55- to 120-fold greater than those observed for the A. fumigatus CYP51 enzymes, albeit not as poor an inhibitor of HsCYP51 as voriconazole with an IC50 value of 112 µM. Sterol analysis of triazole-treated A. fumigatus Af293 cells confirmed that isavuconazole and voriconazole both inhibited cellular CYP51 activity with the accumulation of 14-methylated sterol substrates and depletion of ergosterol levels. Isavuconazole elicited a stronger perturbation of the sterol composition in A. fumigatus Af293 than voriconazole at 0.0125 µg/mL, indicating increased potency. However, complementation studies in Saccharomyces cerevisiae using strains containing AfCYP51A and AfCYP51B showed isavuconazole to be equally as effective at inhibiting CYP51 activity as voriconazole. These in vitro studies suggest that isavuconazole is an effective alternative to voriconazole as an antifungal agent against the target CYP51 in A. fumigatus.

Item Type: Article
Date Type: Publication
Schools: Biosciences
Publisher: Elsevier
ISSN: 0924-8579
Date of First Compliant Deposit: 8 July 2022
Date of Acceptance: 10 July 2019
Last Modified: 26 Aug 2022 11:45

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