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

## TL;DR

Researchers designed and tested new compounds that target a protein in bacteria to reduce biofilm formation, which is a major cause of antibiotic resistance.

## Contribution

A novel class of nature-inspired compounds targeting WrbA for biofilm modulation was computationally designed and experimentally validated.

## Key findings

- The compounds showed good-to-excellent binding affinity to WrbA as measured by MST.
- They modulated biofilm formation in E. coli and S. aureus, possibly through ROS production.
- ROS levels appear to be a key factor in biofilm regulation.

## Abstract

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 K
d 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.

Nature‐inspired WrbA binders for biofilm modulation were designed and synthesized, utilizing computational methods to optimize and select key analogs. The resulting compounds exhibited varying effects on biofilm growth, with reactive oxygen species (ROS) levels likely playing a key role in regulating biofilm responses.