Meroterpenoids from Rhododendron dauricum and the self-assembly driven antibacterial enhancement of grifolin

Infections caused by pathogenic bacteria, particularly Staphylococcus aureus and Escherichia coli, present severe challenges to public health due to their virulence and persistence. The search for novel antimicrobial scaffolds from natural sources is a critical strategy to combat these threats. Rhododendron dauricum, an economic plant resource with a unique chemical profile, has recently garnered attention for its potential antimicrobial properties; however, the effective utilization of its bioactive metabolites is often hindered by poor solubility. In this study, nine meroterpenoids, daurichromenes M-R (1-6), rhodonoids NP (8-10), along with four known analogues (7 and 11-13) and two known triterpenoids (14-15) were isolated from the twigs and leaves of R. dauricum. The structures of undescribed compounds were identified through the analysis of spectroscopic data (MS, UV, NMR), comparison of the experimental and calculated ECD data, modified Mosher's method, and Snatzke's method. Addressing the limitations of natural product application, we discovered that the major constituent, grifolin (7), spontaneously self-assembles into carrier-free nanoparticles. Unlike its monomeric form, which exhibits weak biological activity, grifolin nanoparticles (GNPs) exhibited dose-dependent antimicrobial activity against Staphylococcus aureus, with a minimum inhibitory concentration (MIC) of 125 μg/mL. Molecular dynamics (MD) simulations and UV-vis analysis demonstrated that GNPs self-assemble via molecular aggregation driven by π-π stacking, hydrogen bonding, and electrostatic interactions, leading to the formation of nanofiber clusters. Crucially, this carrier-free nanotechnology improves the stability of bioactive compounds without introducing non-degradable synthetic carriers. This study not only enriches the chemical diversity of R. dauricum but also provides a structure-based, green chemistry strategy for designing self-assembling bacteriostatic agents to unlock the therapeutic potential of natural products against bacterial pathogens.