Quorum sensing-associated bacterial phenazines are potential ligands of human α1-acid glycoprotein

Abstract

α₁-Acid glycoprotein (AGP) is a prominent acute phase component of blood plasma and extravascular fluids. As a member of the immunocalins, AGP exerts protective effects against Gram-negative bacterial infections but the underlying molecular mechanisms still need to be elucidated. Notably, the chemical structures of phenothiazine, phenoxazine and acridine type ligands of AGP are similar to those of phenazine compounds excreted by the opportunistic human pathogen Pseudomonas aeruginosa and related bacterial species. These molecules, like pyocyanin, act as quorum sensing-associated virulence factors and are important contributors to bacterial biofilm formation and host colonisation. Molecular docking simulations revealed that these agents fit into the multi-lobed cavity of AGP. The binding site is decorated by several aromatic residues which seem to be essential for molecular recognition of the ligands allowing multifold π–π and CH–π interactions. The estimated affinity constants (~10⁵ M⁻¹) predict that these secondary metabolites could be trapped inside the β-barrel of AGP which in turn could reduce their cytotoxic effects and disrupt the microbial QS network, facilitating the eradication of bacterial infections.