Novel cationic dihydropyrrol-2-one compounds as antimicrobial agents and quorum sensing inhibitors

Abstract

Antimicrobial resistance has grown to become a global crisis consistently participating in the death of millions worldwide and accumulating costs on healthcare. Quorum sensing inhibition is a new alternative antimicrobial strategy that has been gaining attention due to its ability to suppress the resistance of Pseudomonas aeruginosa (PA). This approach shows great potential in overcoming bacterial resistance and could provide a much needed substitute to conventional antibiotics in the future. PA has 3 main quorum sensing systems of which the Las system has been identified to be the most viable therapeutic target. In this study, we report the synthesis of a library of novel broad-spectrum quorum sensing inhibitors from the dihydropyrrol-2-one scaffold to form urea and imidazolium analogues. Molecular docking was performed in parallel to synthesis to aid design. It also confirmed that the molecules comfortably occupy the ligand binding domain in addition to potential key interactions commonly present in LasR inhibitors. As predicted, these compounds displayed low bactericidal effects against P. aeruginosa with most compounds exhibiting MIC of >250 μM, while maintaining moderate activity towards Escherichia coli with the most potent compound having an MIC of 32 μM. The greatest bactericidal effects were present on Staphylococcus aureus with the thiourea based molecule 10c showed the highest antibacterial activity with MIC of 16 µM. Furthermore, several molecules displayed highly potent quorum sensing inhibitory activity with compounds 10g and 9e both demonstrating over 70 % inhibition respectively of the LasR system at 16 µM. These compounds also expressed inhibition of pyocyanin within P. aeruginosa and haemolytic assay indicates a low level of cell lysis and hence low toxicity of the compounds, further demonstrating the potential of these novel compounds.