Coumarins disrupt cell-cell communication for control of pathogenesis and virulence in ESKAPEEs and fungal opportunists

Intricate communication networks and sensing systems underpin the complexity of microbe-host interactions, enabling spatiotemporal control of optimised microbe-host consortia in a diverse range of ecosystems. A central component of these complex interactomes has been the signalling events that enable recognition of host and microbe, whether that niche be clinical or environmental, human or plant. Coumarins have emerged 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 signal interference and control of pathogenesis in bacterial and fungal pathogens, uncovering an important hydroxylation-motif in the specific inhibition of two Pseudomonas aeruginosa interspecies and interkingdom communication molecules. Characterisation of the anti-biofilm activity of coumarins revealed changes in exopolysaccharide production independent of the initial attachment phenotype. Molecular modelling provides an insight into the receptor binding dynamics of three closely related natural coumarins, suggesting an intricate and highly specific host-microbe interaction at the species level. As the very real threat of antimicrobial resistance continues to shadow our horizons, phytochemicals such as coumarins have potential to deliver an ecological solution to dysbiosis in the host-microbe interaction. ImportanceNatural ecosystems rely on homeostatic interactions between the kingdoms of life to ensure sustainable and balanced communities can persist. Plant-derived coumarins have recently emerged as playing an important role in shaping microbial communities, presenting a remarkable chemical diversity that can influence the behaviour of bacteria and fungi. At the same time, one of the major challenges to human health continues to be the spread of antimicrobial resistance and the parallel absence of a concerted effort to source and produce new antibiotics at industrial scale. Therefore, new approaches to the control of infection are required, and an ecosystem-level lens may offer one such innovative intervention. Coumarins have the potential to neutralise the very mechanisms used by bacteria and fungi to cause infection leading to morbidity and mortality in hosts ranging from plant to animals. Here we present a mechanistic insight into how effective these molecules can be in targeting keystone pathogens termed the ESKAPEEs and their fungal counterparts.