The small molecule regacin binds a conserved pocket in RegA to inhibit the expression of bacterial virulence factors

Authors

Bollinger, C. M., Midgett, C. R., Talbot, K. M., Lawhern, G. V., Munson, G.

Abstract

Antivirulence therapeutics are a promising strategy to combat rising antimicrobial resistance. Transcription factor proteins have shown merit as antivirulence drug targets, as demonstrated by the small molecule Savirin. Regacin was identified as a potent inhibitor of the AraC-family virulence regulator (AraC-VR) RegA of Citrobacter rodentium, providing proof-of-concept for targeting AraC-VR family members in related human enteric pathogens. The structural basis of RegA inhibition by regacin was previously undefined and could prove essential for future drug design campaigns targeting AraC-VR family members. This work reveals that RegA is structurally similar to its homologs ToxT and Rns, including a conserved ligand-binding pocket in the N-terminal domain. A regacin-RegA co-crystal structure shows regacin binds within this pocket, with some heterogeneity in binding pose. Finally, structure-guided mutagenesis of key pocket residues, validated using a {beta}-galactosidase reporter assay, confirmed their role in regacin-mediated inhibition. Together, these findings define the regacin binding site, suggest a molecular basis of RegA inhibition, and provide a framework for future inhibitor design targeting this conserved pocket in other virulence regulators in human enteric pathogens.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 13 Sep 2026.

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