Oxazolidinones: a new chemical class of fungicides and inhibitors of mitochondrial cytochrome bc1function

Famoxadone is a preventative and curative fungicide recently commercialized for plant-disease control. The molecule and its oxazolidinone analogs are potent inhibitors of mitochondrial ubiquinol : cytochrome c oxidoreductase (cytochrome bc1) and they bind in the Q0 site of the enzyme near the low potential heme of cytochrome b. Inhibitor binding constants for five mutant cytochrome bc1 enzymes from Saccharomyces cerevisiae having single amino acid changes in their apocytochrome b located near the low potential heme were compared with their two parental wild-type enzymes. The five individual amino acid changes altered the inhibition constants for the inhibitors famoxadone, myxothiazol, azoxystrobin, and kresoxim-methyl in dissimilar fashion. The log scale differences in binding constants relative to those of their parentals provide fingerprints for the effects of the amino acid changes on binding of the individual inhibitors, thus reflecting the structural diversity of the inhibitors.