Thermodynamic-driven supramolecular transition from nanofibers to nanospheres: morphology-dependent antibacterial specificity of herb medicines

Abstract Background Scutellariae Radix (SR) and Coptidis Rhizoma (CR) are classic drug pairs used in clinical practice for clearing heat and drying dampness, purging fire for removing toxin. By further studying the mechanism of compatibility of SR and CR from the perspective of thermodynamically driven supramolecular phase transition, we could reveal the interaction between its pharmacodynamic components, and provide scientific basis for improving TCM efficacy. Methods The SR-CR and its main components baicalin-berberine (BA-BBR) were taken as the research objects. The morphology of the mechanically mixed samples was characterized by malvern particle size analyzer and scanning electron microscope. UHPLC-Q-Orbitrap HRMS technology was employed to analyze the material basis of each mechanically mixed sample. ITC was used to investigate the effect of temperature on the binding ability between SR and CR. The structural differences of supramolecules in different morphology were explored by molecular dynamics simulation. Finally, in vitro antibacterial models ( E. faecium and B. subtilis , S. aureus ) were used to evaluate the antibacterial activities of the mechanically mixed samples and non-targeted metabolomics was used to explore the differences in antibacterial mechanisms. Results The mechanical mixtures formed nanofibers (NFs), while heating induced a transition to nanospheres (NPs). Molecular dynamics simulations revealed that enhanced hydrogen bonding and tighter molecular packing under thermal conditions drove this morphological shift. In vitro antibacterial assays and non-targeted metabolomics showed NPs exhibited superior inhibition against Staphylococcus aureus by disrupting amino acid biosynthesis and metabolism, whereas NFs suppressed Bacillus subtilis via physical entanglement and interfered with energy metabolism. Conclusion Driven by thermal energy, the existence form of supramolecules changed from NFs to NPs and the morphology of the formed supramolecules was maintained during their interaction with bacteria, further affected the biological activity. Graphical Abstract