Toxic eburicol accumulation drives the antifungal activity of azoles against Aspergillus fumigatus

Hesham Elsaman, Evgeny Golubtsov, Sean Brazil, Natanya Ng, Isabel Klugherz, Ronny Martin, Karl Dichtl, Christoph Müller and Johannes Wagener ()
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Hesham Elsaman: Julius-Maximilians-Universität Würzburg
Evgeny Golubtsov: Julius-Maximilians-Universität Würzburg
Sean Brazil: the University of Dublin
Natanya Ng: the University of Dublin
Isabel Klugherz: Ludwig-Maximilians-Universität München
Ronny Martin: Julius-Maximilians-Universität Würzburg
Karl Dichtl: Ludwig-Maximilians-Universität München
Christoph Müller: Ludwig-Maximilians-Universität München
Johannes Wagener: Julius-Maximilians-Universität Würzburg

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Azole antifungals inhibit the sterol C14-demethylase (CYP51/Erg11) of the ergosterol biosynthesis pathway. Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold Aspergillus fumigatus strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3β,6α-diol, the “toxic diol” responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in A. fumigatus. While ERG3-lacking yeasts are azole resistant, ERG3-lacking A. fumigatus becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly “toxic diol”. We propose that the mode of action of azoles against A. fumigatus relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation.

Date: 2024
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DOI: 10.1038/s41467-024-50609-1

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