Coumarins Disrupt Cell-Cell Communication and Virulence in Priority Pathogens: Targeting the PQS Signalling System in...

Cell-to-cell communication in microbial systems is known for its vital role in cellular signalling and gene expression. A specific form termed Quorum Sensing (QS) has received considerable attention since its discovery in the marine symbiont Aliivibrio fischeri. QS-controlled microbial functions are associated with bacterial virulence, pathogenicity, host-microbe interactions, and biofilm development. Interference in these signalling systems can modulate microbial virulence and pathogenicity, and microbial infection caused by drug-resistant pathogens. Plant-derived phytochemicals are considered a promising candidate, with coumarins emerging as significant plant-derived signalling molecules shaping microbiome dynamics and pathogen behaviours from a broad spectrum of ecosystems. Here we explored the role of natural and synthetic coumarin compounds in the control of signalling and virulence traits in Pseudomonas aeruginosa and other priority bacterial pathogens, including the fungal opportunist Aspergillus fumigatus. We uncovered an important 'hydroxylation-bias' favouring coumarin, umbelliferone (7-OH), and 6-hydroxy-coumarin (6-OH) in the specific competitive inhibition of the Pseudomonas Quinolone Signal (PQS), associated with reduced activity of a PqsR translational fusion and suppression of pyocyanin production. Conversely, while esculetin (6,7-OH) was most effective at Acyl Homoserine Lactone (AHL) QS biosensor inhibition, it did not affect PQS production. Anti-biofilm activity of coumarins against P. aeruginosa was independent of initial attachment but linked to changes in exopolysaccharide production. As the very real threat posed by antimicrobial resistance persists, these data support a role for phytochemicals such as coumarins in delivering an ecological solution to dysbiosis in the host-microbe interaction.