Nature‐Inspired Compounds Targeting Escherichia coli WrbA as Biofilm‐Modulating Agents: Computational Design, Synthesis, and Biological Evaluation

Biofilms pose significant challenges in multiple settings due to their resistance to conventional treatments. In this study, we designed and synthesized a novel class of nature-inspired 5,7-dihydroxy-2,2-dimethylchroman-4-one derivatives as binders of WrbA, a potential target for biofilm modulation. Using a structure-based computational approach, a small library of analogs with varied amide moieties was developed and synthesized. The evaluation of their binding affinity to WrbA demonstrated good-to-excellent Kd values, as confirmed by microscale thermophoresis (MST). Antibiofilm assays against Escherichia coli and Staphylococcus aureus revealed different modulating effects on biofilm formation, conceivably linked to ROS production. These findings emphasize the importance of ROS levels in biofilm, as well as the pivotal role of WrbA as a target in its regulation.