Computer-aided drug design for discovery of small-molecule inhibitors of N-acyl-homoserine lactone synthase in Aromonas hydrophila

Abstract:

[Background] The N-acyl-homoserine lactone synthase AhyⅠ plays a critical role in regulating the production of virulence in Aeromonas hydrophila biofilm. [Objective] To reveal the structure of AhyⅠ, so as to discover effective inhibitors that can disrupt bacterial pathogenicity at the source. [Methods] We constructed the three-dimensional structure of AhyⅠ by employing homology modeling and molecular dynamics simulation with a resolved protein structure as a template. On the basis of previous research results, we selected 214 candidate ligands including two highly effective inhibitors (NOO and MTA) and active components from Chinese herbal medicines to undergo molecular docking with the receptor protein. [Results] Through this process, we identified four potential inhibitors. The minimum inhibitory concentration (MIC), bacterial growth curve, violacein production, biofilm formation, extracellular protease activity, and bacterial swarming and swimming performance showed that artemisinin served as a highly efficient inhibitor of A. hydrophila quorum sensing. [Conclusion] Artemisinin from the Chinese herbal medicine serves the prevention and treatment of infections of waterborne bacteria in the aquaculture industry, holding a promising prospect for the treatment of bacterial infections in the future.