Research Article: Genetic Variation in Plant CYP51s Confers Resistance against Voriconazole, a Novel Inhibitor of Brassinosteroid-Dependent Sterol Biosynthesis

Date Published: January 15, 2013

Publisher: Public Library of Science

Author(s): Wilfried Rozhon, Sigrid Husar, Florian Kalaivanan, Mamoona Khan, Markus Idlhammer, Daria Shumilina, Theo Lange, Thomas Hoffmann, Wilfried Schwab, Shozo Fujioka, Brigitte Poppenberger, Gloria Muday.


Brassinosteroids (BRs) are plant steroid hormones with structural similarity to mammalian sex steroids and ecdysteroids from insects. The BRs are synthesized from sterols and are essential regulators of cell division, cell elongation and cell differentiation. In this work we show that voriconazole, an antifungal therapeutic drug used in human and veterinary medicine, severely impairs plant growth by inhibiting sterol-14α-demethylation and thereby interfering with BR production. The plant growth regulatory properties of voriconazole and related triazoles were identified in a screen for compounds with the ability to alter BR homeostasis. Voriconazole suppressed growth of the model plant Arabidopsis thaliana and of a wide range of both monocotyledonous and dicotyledonous plants. We uncover that voriconazole toxicity in plants is a result of a deficiency in BRs that stems from an inhibition of the cytochrome P450 CYP51, which catalyzes a step of BR-dependent sterol biosynthesis. Interestingly, we found that the woodland strawberry Fragaria vesca, a member of the Rosaceae, is naturally voriconazole resistant and that this resistance is conferred by the specific CYP51 variant of F. vesca. The potential of voriconazole as a novel tool for plant research is discussed.

Partial Text

Higher plants synthesize a complex mixture of small molecular weight compounds, which act as signaling molecules in low quantities to regulate growth and development. One group of plant growth regulatory substances is the brassinosteroids (BRs), steroid hormones similar in their structure to steroid hormones of mammals and ecdysteroids of insects [1]. The BRs regulate cell elongation, cell division and cell differentiation and thereby coordinate developmental programs leading to morphogenesis [2], [3].

In recent years significant progress has been made in our understanding of sterol biosynthesis and BR biosynthesis and signaling in plants, which was made possible largely by the use of molecular genetics in the model species Arabidopsis thaliana[3], [53], [10], [5]. However, sterol- and BR-deficient mutants are available for only a few plant species with agro-economical interest as classical mutant isolation is hampered in many crops by their polyploidy. Chemical inhibitors are an attractive option to circumvent this problem. Moreover, their application to different genetic backgrounds is possible without the need for time-consuming crossing and a transient application allows studying the impact of targeted pathways in certain tissues and developmental stages [19], [20].