α-Bisabolol from Chamomile – A specific ergosterol biosynthesis inhibitor?

Abstract

Summary There is a strong need for new antifungal agents with a different mode of action due to the therapeutic limitations of existing drugs and the development of fungal resistances ([ NIAID , The second NIAID workshop in medical mycology: molecular and immunologic approaches to the diagnosis and treatment of systemic mycoses, http://www.niaid.nih.gov/dmid/meetings/mycology94/fungal.htm (2001)]). Mammalians, plants and fungi produce at least different cell wall sterols from common precursors. No antifungal drug is known that specifically prevents the formation of the fungal ergosterol, without affecting sterol biosynthesis at early, common stages ( DiDomenico , B., Novel antifungal drugs, Curr Opin Microbiol 1999;2:509–15; Walsh TJ, Viviani MA, Arathoon E, Chiou C, Ghannoum M, Groll AH, et al., New target and delivery systems for antifungal therapy, Med Mycol 2000;38(Suppl. I):335–47). To find new inhibitors that may inhibit ergosterol biosynthesis, a query of a database on antimicrobials (Pauli, A., AmicBase 2005. Weinheim, New York: Wiley, 2005a; Pauli, A., Anticandidal low molecular compounds from higher plants with special reference to compounds from essential oils. Med Res Rev doi:10.1002/med.20050 ; 2005b) was performed with substructures of intermediates of ergosterol biosynthesis. As a result a series of Candida albicans-inhibiting compounds were identified that all possess the side chain of zymosterol as a substructure; their anticandidal activity was found to be increased with increase of their molecular volume. The entire structure of the Chamomile constituent α-bisabolol is found as a substructure in similar form within zymosterol. It was therefore concluded that compounds of this type interfere with ergosterol biosynthesis at the level of zymosterol and prevent the formation of fecosterol from zymosterol, which is the first fungi specific step in ergosterol biosynthesis. Due to the low toxicity of α-bisabolol (Schilcher H, Wirkungsweise und Anwendungsformen der Kamillenbluten, BMV Berliner Medizinische Verlagsanstalt GmbH, Berlin; 2004) the compound comes into question as a therapeutic agent and may serve as a lead compound in the development of new antifungal drugs.