A Nonbactericidal Zinc‐Complexing Ligand as a Biofilm Inhibitor: Structure‐Guided Contrasting Effects on Staphylococcus aureus Biofilm

Zinc‐complexing ligands are prospective anti‐biofilm agents because of the pivotal role of zinc in the formation of Staphylococcus aureus biofilm. Accordingly, the potential of a thiosemicarbazone (compound C1) and a benzothiazole‐based ligand (compound C4) in the prevention of S. aureus biofilm formation was assessed. Compound C1 displayed a bimodal activity, hindering biofilm formation only at low concentrations and promoting biofilm growth at higher concentrations. In the case of C4, a dose‐dependent inhibition of S. aureus biofilm growth was observed. Atomic force microscopy analysis suggested that at higher concentrations C1 formed globular aggregates, which perhaps formed a substratum that favored adhesion of cells and biofilm formation. In the case of C4, zinc supplementation experiments validated zinc complexation as a plausible mechanism of inhibition of S. aureus biofilm. Interestingly, C4 was nontoxic to cultured HeLa cells and thus has promise as a therapeutic anti‐biofilm agent. The essential understanding of the structure‐driven implications of zinc‐complexing ligands acquired in this study might assist future screening regimes for identification of potent anti‐biofilm agents.