Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance

Abstract

Ergosterol, the major sterol of fungal membranes, is essential for developmental growth and the main target of antifungals that are currently used to treat fatal fungal infections. Emergence of resistance to existing antifungals is a current problem and several secondary resistance mechanisms have been described in Aspergillus fumigatus clinical isolates. A full understanding of ergosterol biosynthetic control therefore appears to be essential for improvement of antifungal efficacy and to prevent antifungal resistance. An ergosterol biosynthesis pathway in A. fumigatus has been proposed with 14 sterol intermediates resulting in ergosterol and another secondary final compound C-24 ethyl sterol. Transcriptomic analysis of the A. fumigatus response to host-imposed stresses or antifungal agents is expanding our understanding of both sterol biosynthesis and the modes of action of antifungal drugs. Ultimately, the identification of new targets for novel drug design, or the study of combinatorial effects of targeting sterol biosynthesis together with other metabolic pathways, is warranted.

Keywords: Aspergillus; antifungal drugs; ergosterol biosynthesis; resistance mechanisms; transcriptome.

FIGURE 1

Ergosterol biosynthetic pathway. Sterols of A. fumigatus wild-type strain (CM-237), and Δcyp51A, Δcyp51B (marked in green), Δerg3A, Δerg3B, and Δerg3C (marked in red) derived mutant strains. Sterols are clustered and represented in cake plots as the percentage of total sterols: Δ5 sterols (1, 2, 3, 4, 6, 8 in gray), C-4/C-14 methyl sterols (11, 12, 13, 14 in green), Δ7 sterols (5, 7, 9 in red), and ethyl sterols (10 in purple) according to the sterol identification in A. fumigatus (Table 1).