Mode of action of famoxadone

Famoxadone is a preventative and curative fungicide recently developed for plant disease control. The molecule and its oxazolidinone analogs (OADs) ar e potent inhibitors of mitochondrial electron transport, specifically inhib iting the function of the enzyme ubiquinol :cytochrome c oxidoreductase (cy tochrome bc(1)). Visible absorbance spectral studies on the purified enzyme suggested that famoxadone bound close to the low potential heme of cytochr ome b. This binding mode was confirmed in competitive binding experiments b y studying the displacement of a radiolabelled OAD from submitochondria. EP R studies on the binding of famoxadone to submitochondria and purified be, suggested its binding mode was more like that of myxothiazol than that of s tigmatellin (ligands known to bind near the low potential heme), Zoospores of Phytophthora infestans, when given low concentrations of famoxadone and other OADs, were observed to cease oxygen consumption and motility within s econds and later the cells disintegrated, releasing the cellular contents. Famoxadone was a potent inhibitor of the growth of Saccharomyces cerevisiae when grown on non-fermentable carbon sources and it was an approximately 5 0-fold less potent inhibitor of growth when the yeast was grown on a fermen table carbon source, glucose. Such physiological observations are consisten t with the loss of mitochondrial function imposed by famoxadone and OADs. S ingle amino acid changes in the apocytochrome b of baker's yeast cytochrome b located near the low potential heme altered the inhibition constants for the inhibitors famoxadone, myxothiazol, azoxystrobin and kresoxim-methyl d ifferentially, thus strongly suggesting different binding interactions of t he protein with the inhibitors, (C) 1999 Society of Chemical Industry.