Summary Colorectal cancer pathogenesis and progression is associated with the presence of Fusobacterium nucleatum and the reduction of acetylated derivatives of spermidine, as well as dietary components such as tannin‐rich foods. We show that a new tannase orthologue of F. nucleatum (TanBF nn ) has significant structural differences with its Lactobacillus plantarum counterpart affecting the flap covering the active site and the accessibility of substrates. Crystallographic and molecular dynamics analysis revealed binding of polyamines to a small cavity that connects the active site with the bulk solvent which interact with catalytically indispensable residues. As a result, spermidine and its derivatives, particularly N 8 ‐acetylated spermidine, inhibit the hydrolytic activity of TanBF nn and increase the toxicity of gallotannins to F. nucleatum . Our results support a model in which the balance between the detoxicant activity of TanBF nn and the presence of metabolic inhibitors can dictate either conducive or unfavourable conditions for the survival of F. nucleatum .