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

Zinc-complexing ligands are prospective antibiofilm agents, given the pivotal role of zinc in the formation of Staphylococcus aureus biofilm. To this end, the potential of a thiosemicarbazone (C1) and a benzothiazole-based ligand (C4) in the prevention of S. aureus biofilm formation was assessed. C1 displayed a bimodal activity as it hindered biofilm formation only at low concentrations and promoted biofilm growth at higher concentrations. In case of C4, a dose-dependent inhibition of S. aureus biofilm growth was observed. Atomic force microscope analysis suggested that at higher concentrations, C1 formed globular aggregates, which perhaps formed a substratum that favored adhesion of cells and biofilm formation. In case of C4, zinc supplementation experiments validated zinc-complexation as the plausible mechanism of inhibiting S. aureus biofilm. Interestingly, C4 was non-toxic to cultured HeLa cells and thus holds promise as a therapeutic antibiofilm agent. The essential understanding of the structure-driven implications of zinc-complexing ligands acquired in this study would assist future screening regimes for identification of potent antibiofilm agents.