Miconazole, more to it than merely inhibition of ergosterol biosynthesis

Ref ID: 12718

Author: Francois1, E.J.A., Thevissen1, K., Vandercappellen1, J., Borgers2, M., Van Minnebruggen2, G., Cammue1, B.P.A.

Author address:

1Katholic University Leuven, HEVERLEE, Belgium 2Barrier Therapeutics nv, GEEL,
Belgium

Full conference title:

3rd Trends in Medical Mycology

Date: 28 October 2014

Abstract:

The synthetic class of azole antimycotics constitutes the largest group of antifungal agents currently in clinical use. The generally accepted mode of action of azoles is the inhibition of 14α -lanosterol demethylase, a key enzyme in ergosterol biosynthesis, resulting in depletion of ergosterol and accumulation of toxic 14α -methylated sterols in
membranes of susceptible yeast species. Recently, we and other research groups
could demonstrate that generation of reactive oxygen species (ROS) is important for the antifungal activity of miconazole (1,2), pointing to an ancillary mode of action for this azole. In order to further analyze the possible involvement of additional cellular processes in the miconazole antifungal action, we performed a genome-wide screen to
identify genes involved in miconazole sensitivity. To this end, we screened the
complete set of haploid Saccharomyces cerevisiae deletion mutants for miconazole resistance. As such, we could demonstrate that S. cerevisiae deletion mutants affected in sphingolipid and ergosterol biosynthesis are at least 10-fold resistant to miconazole. This suggests a possible involvement of lipid rafts, membrane patches consisting of
ergosterol and sphingolipids, in the antifungal mode of action of miconazole. In this regard, we analyzed whether lipid raft disturbing agents such as edelfosine and methyl-beta-cyclodextrin modulate miconazole activity. Indeed, we could demonstrate that miconazole activity is antagonized by disruption of the lipid rafts. Moreover, we could demonstrate that ROS induction by miconazole is antagonized by both agents, indicating that the miconazole-induced ROS production is dependent on functional lipid rafts. In conclusion, lipid rafts and ROS induction are importantdeterminants for miconazole antifungal action. Their possible interplay in miconazole antifungal activity
will be discussed.
References:
1. François et al. (2006) Anti-Infect. Agents Med. Chem. 5, 3-13.
2. Kobayashi et al. (2002) Antimicrob. Agents Chemother. 46, 3113-3117.

Abstract Number: P052

Slides: y

Conference Year: 2007

Link to conference website: NULL

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