Resolving host-guest interactions between pillararenes and homoserine lactones to restrain bacterial quorum sensing

Using supramolecular host molecules to hinder bacterial quorum sensing (QS) is a potential approach in circumventing antimicrobial resistance (AMR). The emergent family of pillararenes offers promising candidates for binding homoserine lactones (HSLs), signaling molecules used by gram-negative species, including WHO critical-priority antibiotic-resistant bacteria. Here, we compare seven cationic pillararenes against four HSLs, from (supra)molecular interactions to biological assays. Complexation, characterized by dye displacement assay and NMR spectroscopy, complemented by all-atom molecular dynamics (MD) simulations, was compared to effects in biological systems, studied using a bacterial HSL reporter system as well as biofilm and pyocyanin assays as models of QS-mediated virulence. HSL binding improves approximately 10-fold versus previous reports with a hydroxyl-functionalized pillararene, and a deeper-cavity host with marked preference for the longest-tailed HSL is identified. Successful HSL capture is directly reflected as impaired biofilm formation and pyocyanin production and improved healing in open wound in vivo models. [Display omitted] •Pillararene host molecules are studied for binding bacterial signaling molecules•Characterization is carried out at molecular, microbial, and animal levels•Pillararenes bind homoserine lactone signal molecules via host-guest chemistry•Molecular binding reflected as impaired virulence, improved healing in a wound model Luotonen et al. report on a series of pillararenes, “host” molecules that can capture bacterial signal compounds in a molecular pocket to disrupt communication mechanisms involved in disease. Linking chemical and biological analyses reflected a strong link between homoserine lactone capture and blocking bacterial behaviors involved in disease.