Molecular Mechanism of Fusarium Fungus Inhibition by Phenazine-1-carboxamide

Fusarium head blight caused by Fusarium
graminearum is a devastating disease in
wheat that seriously endangers food
security and human health. Previous studies have found that the secondary
metabolite phenazine-1-carboxamide produced by biocontrol bacteria
inhibited F. graminearum by binding
to and inhibiting the activity of histone acetyltransferase Gcn5
(FgGcn5). However, the detailed mechanism of this inhibition remains
unknown. Our structural and biochemical studies revealed that phenazine-1-carboxamide
(PCN) binds to the histone acetyltransferase (HAT) domain of FgGcn5
at its cosubstrate acetyl-CoA binding site, thus competitively inhibiting
the histone acetylation function of the enzyme. Alanine substitution
of the residues in the binding site shared by PCN and acetyl-CoA not
only decreased the histone acetylation level of the enzyme but also
dramatically impacted the development, mycotoxin synthesis, and virulence
of the strain. Taken together, our study elucidated a competitive
inhibition mechanism of Fusarium fungus by PCN and provided a structural
template for designing more potent phenazine-based fungicides.