Marine-derived phlorotannins: sustainable inhibitors of multiple virulence factors in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen in diverse environments, causing plant, animal, and human infections. Its remarkable ability to resist antibiotics and deploy multiple virulence strategies is attributed to its large genome, horizontal gene transfer, and complex regulatory networks. In this study, we comprehensively investigated 15 structurally distinct phlorotannins against 18 major virulence-associated proteins, such as quorum-sensing proteins, adhesion proteins, exotoxins, siderophore receptors, secretion system components, proteases, motility, and biofilm formation. Molecular docking and 50-ns molecular dynamics simulations revealed that compounds such as 2-phloroeckol, 7-phloroeckol, phlorofucofuroeckol A, and phlorofucofuroeckol B formed strong and stable interactions with critical targets, type IV pilus biogenesis factor PilY1, ferripyoverdine receptor, and phenazine-1-carboxylate-methyltransferase, with binding free energies as low as - 12.24 kcal/mol. These compounds exhibited a wide range of non-covalent interactions, including hydrogen bonding and π-π stacking, with essential active site residues in target proteins. Drug-likeness and environmental safety assessments utilizing the pkCSM and VEGA (Q)SAR models revealed high oral bioavailability, low toxicity, minimal cytochrome P450 interactions, and mostly non-mutagenic profiles. This study reveals phlorotannins as prospective eco-friendly alternatives for reducing P. aeruginosa infection by addressing a broad spectrum of virulence factors with ecologically benign and biodegradable natural compounds.