In silico identification of new potential inhibitors of quorum sensing by Gram-positive bacteria through specialized molecular docking

Abstract

Quorum sensing is the process by which bacterial cells can communicate by producing substances to regulate viable processes such as gene expression, virulence, and biofilm formation. Gram-positive bacteria such as Staphylococcus aureus and Enterococcus faecalis have specific enzymes (autoinducers) that control the quorum sensing system. Sortase A is a surface protein that regulates virulence and cell‒cell communication in Gram-positive bacteria. To interfere with this system and reduce virulence and cell‒cell communication, quorum sensing inhibitors are used, which are nonantibiotic substances. In this study, we aimed to use Food and Drug Administration-approved drugs (analgesics and antipsychotics) and investigate their activity using molecular docking and microbiological assays against both quorum sensing in Gram-positive S. aureus and E. faecalis. This study investigated the quorum sensing inhibitors acetylsalicylic acid and trifluoperazine and evaluated their affinity to the active site of SrtA (PDB:1t2w) using AutoDock Vina software. Agar diffusion and minimum inhibitory concentration tests were performed to experimentally validate the quorum sensing inhibitor activity of acetylsalicylic acid and trifluoperazine. Molecular docking illustrated that acetylsalicylic acid and trifluoperazine have high affinity as quorum sensing inhibitors in both S. aureus and E. faecalis. However, only acetylsalicylic acid showed inhibition activity at 1000 µg/ml in E. faecalis and at 250 µg/ml by the agar well diffusion method in S. aureus. The high affinity of these quorum sensing inhibitors, as presented by the molecular docking and inhibition of growth experiments, are indications of their ability to act as quorum sensing inhibitors and as promising synergistic with nonantibiotic drugs to treat infection.